2024-03-29T05:28:54Zhttp://repository.helmholtz-hzi.de/oai/requestoai:repository.helmholtz-hzi.de:10033/928492019-08-30T11:35:14Zcom_10033_56876col_10033_56896
Characterization of the interferon-producing cell in mice infected with Listeria monocytogenes.
Stockinger, Silvia
Kastner, Renate
Kernbauer, Elisabeth
Pilz, Andreas
Westermayer, Sandra
Reutterer, Benjamin
Soulat, Didier
Stengl, Gabriele
Vogl, Claus
Frenz, Theresa
Waibler, Zoe
Taniguchi, Tadatsugu
Rülicke, Thomas
Kalinke, Ulrich
Müller, Mathias
Decker, Thomas
Max F. Perutz Laboratories, Department of Microbiology and Immunobiology, University of Vienna, Vienna, Austria.
Animals
Antigens, CD
Dendritic Cells
Flow Cytometry
Interferon Regulatory Factor-7
Interferon Type I
Interferon-beta
Listeria Infections
Listeria monocytogenes
Macrophages
Mice
Mice, Inbred C57BL
Phenotype
Reverse Transcriptase Polymerase Chain Reaction
Spleen
Toll-Like Receptor 9
Production of type I interferons (IFN-I, mainly IFNalpha and IFNbeta) is a hallmark of innate immune responses to all classes of pathogens. When viral infection spreads to lymphoid organs, the majority of systemic IFN-I is produced by a specialized "interferon-producing cell" (IPC) that has been shown to belong to the lineage of plasmacytoid dendritic cells (pDC). It is unclear whether production of systemic IFN-I is generally attributable to pDC irrespective of the nature of the infecting pathogen. We have addressed this question by studying infections of mice with the intracellular bacterium Listeria monocytogenes. Protective innate immunity against this pathogen is weakened by IFN-I activity. In mice infected with L. monocytogenes, systemic IFN-I was amplified via IFN-beta, the IFN-I receptor (IFNAR), and transcription factor interferon regulatory factor 7 (IRF7), a molecular circuitry usually characteristic of non-pDC producers. Synthesis of serum IFN-I did not require TLR9. In contrast, in vitro-differentiated pDC infected with L. monocytogenes needed TLR9 to transcribe IFN-I mRNA. Consistent with the assumption that pDC are not the producers of systemic IFN-I, conditional ablation of the IFN-I receptor in mice showed that most systemic IFN-I is produced by myeloid cells. Furthermore, results obtained with FACS-purified splenic cell populations from infected mice confirmed the assumption that a cell type with surface antigens characteristic of macrophages and not of pDC is responsible for bulk IFN-I synthesis. The amount of IFN-I produced in the investigated mouse lines was inversely correlated to the resistance to lethal infection. Based on these data, we propose that the engagement of pDC, the mode of IFN-I mobilization, as well as the shaping of the antimicrobial innate immune response by IFN-I differ between intracellular pathogens.
2010-02-24T12:22:05Z
2010-02-24T12:22:05Z
2009-03
Article
Characterization of the interferon-producing cell in mice infected with Listeria monocytogenes. 2009, 5 (3):e1000355 PLoS Pathog.
1553-7374
19325882
10.1371/journal.ppat.1000355
http://hdl.handle.net/10033/92849
PLoS pathogens
en
oai:repository.helmholtz-hzi.de:10033/960012019-08-30T11:26:42Zcom_10033_56876col_10033_56896
Type I interferon induction is detrimental during infection with the Whipple's disease bacterium, Tropheryma whipplei.
Al Moussawi, Khatoun
Ghigo, Eric
Kalinke, Ulrich
Alexopoulou, Lena
Mege, Jean-Louis
Desnues, Benoit
Université de la Méditerranée, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 6236, Marseille, France.
Animals
Apoptosis
Blotting, Western
Enzyme-Linked Immunosorbent Assay
Fluorescent Antibody Technique
Gene Expression
Gene Expression Profiling
In Situ Nick-End Labeling
Interferon Regulatory Factor-3
Interferon Type I
Macrophage Activation
Macrophages
Mice
Mice, Inbred C57BL
Mice, Knockout
Oligonucleotide Array Sequence Analysis
Reverse Transcriptase Polymerase Chain Reaction
STAT1 Transcription Factor
Signal Transduction
Transfection
Tropheryma
Whipple Disease
Macrophages are the first line of defense against pathogens. Upon infection macrophages usually produce high levels of proinflammatory mediators. However, macrophages can undergo an alternate polarization leading to a permissive state. In assessing global macrophage responses to the bacterial agent of Whipple's disease, Tropheryma whipplei, we found that T. whipplei induced M2 macrophage polarization which was compatible with bacterial replication. Surprisingly, this M2 polarization of infected macrophages was associated with apoptosis induction and a functional type I interferon (IFN) response, through IRF3 activation and STAT1 phosphorylation. Using macrophages from mice deficient for the type I IFN receptor, we found that this type I IFN response was required for T. whipplei-induced macrophage apoptosis in a JNK-dependent manner and was associated with the intracellular replication of T. whipplei independently of JNK. This study underscores the role of macrophage polarization in host responses and highlights the detrimental role of type I IFN during T. whipplei infection.
2010-04-08T13:55:06Z
2010-04-08T13:55:06Z
2010
Article
Type I interferon induction is detrimental during infection with the Whipple's disease bacterium, Tropheryma whipplei. 2010, 6 (1):e1000722 PLoS Pathog.
1553-7374
20090833
10.1371/journal.ppat.1000722
http://hdl.handle.net/10033/96001
PLoS pathogens
en
oai:repository.helmholtz-hzi.de:10033/1341892019-08-30T11:37:23Zcom_10033_56876col_10033_56896
Thogoto virus infection induces sustained type I interferon responses that depend on RIG-I-like helicase signaling of conventional dendritic cells.
Kochs, Georg
Bauer, Stefanie
Vogt, Carola
Frenz, Theresa
Tschopp, Jürg
Kalinke, Ulrich
Waibler, Zoe
Abteilung Virologie, Institut für Medizinische Mikrobiologie und Hygiene, Universität Freiburg, Freiburg, Germany.
Adaptor Proteins, Signal Transducing
Adaptor Proteins, Vesicular Transport
Animals
DEAD-box RNA Helicases
Dendritic Cells
Interferon Type I
Mice
Mice, Inbred C57BL
Mice, Knockout
Models, Immunological
Myeloid Differentiation Factor 88
Orthomyxoviridae Infections
Reverse Transcriptase Polymerase Chain Reaction
Signal Transduction
Thogotovirus
Type I interferon (IFN-α/β) induction upon viral infection contributes to the early antiviral host defense and ensures survival until the onset of adaptive immunity. Many viral infections lead to an acute, transient IFN expression which peaks a few hours after infection and reverts to initial levels after 24 to 36 h. Robust IFN expression often is conferred by specialized plasmacytoid dendritic cells (pDC) and may depend on positive-feedback amplification via the type I IFN receptor (IFNAR). Here, we show that mice infected with Thogoto virus (THOV), which is an influenza virus-like orthomyxovirus transmitted by ticks, mounted sustained IFN responses that persisted up to 72 h after infection. For this purpose, we used a variant of THOV lacking its IFN-antagonistic protein ML, an elongated version of the matrix (M) protein [THOV(ΔML)]. Of note, large amounts of type I IFN were also found in the serum of mice lacking the IFNAR. Early IFN-α expression seemed to depend on Toll-like receptor (TLR) signaling, whereas prolonged IFN-α responses strictly depended on RIG-I-like helicase (RLH) signaling. Unexpectedly, THOV(ΔML)-infected bone marrow-derived pDC (BM-pDC) produced only moderate IFN levels, whereas myeloid DC (BM-mDC) showed massive IFN induction that was IPS-1-dependent, suggesting that BM-mDC are involved in the massive, sustained IFN production in THOV(ΔML)-infected animals. Thus, our data are compatible with the model that THOV(ΔML) infection is sensed in the acute phase via TLR and RLH systems, whereas at later time points only RLH signaling is responsible for the induction of sustained IFN responses.
2011-06-22T14:11:44Z
2011-06-22T14:11:44Z
2010-12
Article
Thogoto virus infection induces sustained type I interferon responses that depend on RIG-I-like helicase signaling of conventional dendritic cells. 2010, 84 (23):12344-50 J. Virol.
1098-5514
20861272
10.1128/JVI.00931-10
http://hdl.handle.net/10033/134189
Journal of virology
en
oai:repository.helmholtz-hzi.de:10033/1428312019-08-30T11:37:44Zcom_10033_56876col_10033_56896
GATA6 promotes angiogenic function and survival in endothelial cells by suppression of autocrine transforming growth factor beta/activin receptor-like kinase 5 signaling.
Froese, Natali
Kattih, Badder
Breitbart, Astrid
Grund, Andrea
Geffers, Robert
Molkentin, Jeffery D
Kispert, Andreas
Wollert, Kai C
Drexler, Helmut
Heineke, Joerg
Medizinische Hochschule Hannover, Klinik für Kardiologie und Angiologie, Institut für Molekularbiologie, Rebirth-Cluster of Excellence, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany.
Animals
Apoptosis
Autocrine Communication
Cells, Cultured
Endothelial Cells
GATA6 Transcription Factor
Gene Expression Regulation
Humans
Mice
Neovascularization, Physiologic
Protein-Serine-Threonine Kinases
Receptors, Transforming Growth Factor beta
Signal Transduction
Smad2 Protein
Transforming Growth Factor beta1
Transforming Growth Factor beta2
Understanding the transcriptional regulation of angiogenesis could lead to the identification of novel therapeutic targets. We showed here that the transcription factor GATA6 is expressed in different human primary endothelial cells as well as in vascular endothelial cells of mice in vivo. Activation of endothelial cells was associated with GATA6 nuclear translocation, chromatin binding, and enhanced GATA6-dependent transcriptional activation. siRNA-mediated down-regulation of GATA6 after growth factor stimulation led to a dramatically reduced capacity of macro- and microvascular endothelial cells to proliferate, migrate, or form capillary-like structures on Matrigel. Adenoviral overexpression of GATA6 in turn enhanced angiogenic function, especially in cardiac endothelial microvascular cells. Furthermore, GATA6 protected endothelial cells from undergoing apoptosis during growth factor deprivation. Mechanistically, down-regulation of GATA6 in endothelial cells led to increased expression of transforming growth factor (TGF) β1 and TGFβ2, whereas enhanced GATA6 expression, accordingly, suppressed Tgfb1 promoter activity. High TGFβ1/β2 expression in GATA6-depleted endothelial cells increased the activation of the activin receptor-like kinase 5 (ALK5) and SMAD2, and suppression of this signaling axis by TGFβ neutralizing antibody or ALK5 inhibition restored angiogenic function and survival in endothelial cells with reduced GATA6 expression. Together, these findings indicate that GATA6 plays a crucial role for endothelial cell function and survival, at least in part, by suppressing autocrine TGFβ expression and ALK5-dependent signaling.
2011-09-21T12:50:32Z
2011-09-21T12:50:32Z
2011-02-18
Article
GATA6 promotes angiogenic function and survival in endothelial cells by suppression of autocrine transforming growth factor beta/activin receptor-like kinase 5 signaling. 2011, 286 (7):5680-90 J. Biol. Chem.
1083-351X
21127043
10.1074/jbc.M110.176925
http://hdl.handle.net/10033/142831
The Journal of biological chemistry
en
oai:repository.helmholtz-hzi.de:10033/1428442019-08-30T11:37:00Zcom_10033_56876col_10033_56896
Regulatory T cells facilitate the nuclear accumulation of inducible cAMP early repressor (ICER) and suppress nuclear factor of activated T cell c1 (NFATc1).
Vaeth, Martin
Gogishvili, Tea
Bopp, Tobias
Klein, Matthias
Berberich-Siebelt, Friederike
Gattenloehner, Stefan
Avots, Andris
Sparwasser, Tim
Grebe, Nadine
Schmitt, Edgar
Hünig, Thomas
Serfling, Edgar
Bodor, Josef
Department of Molecular Pathology, Institute of Pathology, University of Wurzburg, D-97080 Wurzburg, Germany.
Active Transport, Cell Nucleus
Animals
Antibodies
Antigens, CD28
Cell Nucleus
Cyclic AMP
Cyclic AMP Response Element Modulator
Interleukin-2
Lymphocyte Activation
Mice
Mice, Inbred BALB C
Mice, Knockout
NFATC Transcription Factors
Response Elements
T-Lymphocytes, Regulatory
Inducible cAMP early repressor (ICER) is a transcriptional repressor, which, because of alternate promoter use, is generated from the 3' region of the cAMP response modulator (Crem) gene. Its expression and nuclear occurrence are elevated by high cAMP levels in naturally occurring regulatory T cells (nTregs). Using two mouse models, we demonstrate that nTregs control the cellular localization of ICER/CREM, and thereby inhibit IL-2 synthesis in conventional CD4(+) T cells. Ablation of nTregs in depletion of regulatory T-cell (DEREG) mice resulted in cytosolic localization of ICER/CREM and increased IL-2 synthesis upon stimulation. Direct contacts between nTregs and conventional CD4(+) T cells led to nuclear accumulation of ICER/CREM and suppression of IL-2 synthesis on administration of CD28 superagonistic (CD28SA) Ab. In a similar way, nTregs communicated with B cells and induced the cAMP-driven nuclear localization of ICER/CREM. High levels of ICER suppressed the induction of nuclear factor of activated T cell c1 (Nfatc1) gene in T cells whose inducible Nfatc1 P1 promoter bears two highly conserved cAMP-responsive elements to which ICER/CREM can bind. These findings suggest that nTregs suppress T-cell responses by the cAMP-dependent nuclear accumulation of ICER/CREM and inhibition of NFATc1 and IL-2 induction.
2011-09-21T14:08:19Z
2011-09-21T14:08:19Z
2011-02-08
Article
Regulatory T cells facilitate the nuclear accumulation of inducible cAMP early repressor (ICER) and suppress nuclear factor of activated T cell c1 (NFATc1). 2011, 108 (6):2480-5 Proc. Natl. Acad. Sci. U.S.A.
1091-6490
21262800
10.1073/pnas.1009463108
http://hdl.handle.net/10033/142844
Proceedings of the National Academy of Sciences of the United States of America
en
oai:repository.helmholtz-hzi.de:10033/1926222019-08-30T11:24:31Zcom_10033_56876col_10033_56896
IL-18 inhibits growth of murine orthotopic prostate carcinomas via both adaptive and innate immune mechanisms.
Tse, Brian Wan-Chi
Russell, Pamela Joan
Lochner, Matthias
Förster, Irmgard
Power, Carl Andrew
Lowy Cancer Research Centre, University of New South Wales, Sydney, New South Wales, Australia.
Interleukin(IL)-18 is a pleiotrophic cytokine with functions in immune modulation, angiogenesis and bone metabolism. In this study, the potential of IL-18 as an immunotherapy for prostate cancer (PCa) was examined using the murine model of prostate carcinoma, RM1 and a bone metastatic variant RM1(BM)/B4H7-luc. RM1 and RM1(BM)/B4H7-luc cells were stably transfected to express bioactive IL-18. These cells were implanted into syngeneic immunocompetent mice, with or without an IL-18-neutralising antibody (αIL-18, SK113AE4). IL-18 significantly inhibited the growth of both subcutaneous and orthotopic RM1 tumors and the IL-18 neutralizing antibody abrogated the tumor growth-inhibition. In vivo neutralization of interferon-gamma (IFN-γ) completely eliminated the anti-tumor effects of IL-18 confirming an essential role of IFN-γ as a down-stream mediator of the anti-tumor activity of IL-18. Tumors from mice in which IL-18 and/or IFN-γ was neutralized contained significantly fewer CD4(+) and CD8(+) T cells than those with functional IL-18. The essential role of adaptive immunity was demonstrated as tumors grew more rapidly in RAG1(-/-) mice or in mice depleted of CD4(+) and/or CD8(+) cells than in normal mice. The tumors in RAG1(-/-) mice were also significantly smaller when IL-18 was present, indicating that innate immune mechanisms are involved. IL-18 also induced an increase in tumor infiltration of macrophages and neutrophils but not NK cells. In other experiments, direct injection of recombinant IL-18 into established tumors also inhibited tumor growth, which was associated with an increase in intratumoral macrophages, but not T cells. These results suggest that local IL-18 in the tumor environment can significantly potentiate anti-tumor immunity in the prostate and clearly demonstrate that this effect is mediated by innate and adaptive immune mechanisms.
2011-11-30T12:17:30Z
2011-11-30T12:17:30Z
2011
Article
IL-18 inhibits growth of murine orthotopic prostate carcinomas via both adaptive and innate immune mechanisms. 2011, 6 (9):e24241 PLoS ONE
1932-6203
21935389
10.1371/journal.pone.0024241
http://hdl.handle.net/10033/192622
PloS one
en
oai:repository.helmholtz-hzi.de:10033/2003292019-08-30T11:31:49Zcom_10033_56876col_10033_56896
Regulatory T cells control tolerogenic versus autoimmune response to sperm in vasectomy.
Wheeler, Karen
Tardif, Steve
Rival, Claudia
Luu, Brian
Bui, Elise
Del Rio, Roxana
Teuscher, Cory
Sparwasser, Tim
Hardy, Daniel
Tung, Kenneth S K
Department of Pathology and Beirne B Carter Center of Immunology, University of Virginia, Charlottesville, VA 22908, USA.
Animals
Autoantibodies
Autoimmunity
Blotting, Western
Cell Proliferation
Electrophoresis, Polyacrylamide Gel
Immune Tolerance
Male
Membrane Proteins
Mice
Mice, Mutant Strains
Spermatozoa
Statistics, Nonparametric
T-Lymphocytes, Regulatory
Vasectomy
Vasectomy is a well accepted global contraceptive approach frequently associated with epididymal granuloma and sperm autoantibody formation. To understand the long-term sequelae of vasectomy, we investigated the early immune response in vasectomized mice. Vasectomy leads to rapid epithelial cell apoptosis and necrosis, persistent inflammation, and sperm granuloma formation in the epididymis. Vasectomized B6AF1 mice did not mount autoimmune response but instead developed sperm antigen-specific tolerance, documented as resistance to immunization-induced experimental autoimmune orchitis (EAO) but not experimental autoimmune encephalomyelitis. Strikingly, tolerance switches over to pathologic autoimmune state following concomitant CD4(+)CD25(+)Foxp3(+) regulatory T cell (Treg) depletion: unilaterally vasectomized mice produce dominant autoantibodies to an orchitogenic antigen (zonadhesin), and develop CD4 T-cell- and antibody-dependent bilateral autoimmune orchitis. Therefore, (i) Treg normally prevents spontaneous organ-specific autoimmunity induction by persistent endogenous danger signal, and (ii) autoantigenic stimulation with sterile autoinflammation can lead to tolerance. Finally, postvasectomy tolerance occurs in B6AF1, C57BL/6, and A/J strains. However, C57BL/6 mice resisted EAO after 60% Treg depletion, but developed EAO after 97% Treg reduction. Therefore, variance in intrinsic Treg function--a possible genetic trait--can influence the divergent tolerogenic versus autoimmune response to vasectomy.
2012-01-05T15:10:58Z
2012-01-05T15:10:58Z
2011-05-03
Article
Regulatory T cells control tolerogenic versus autoimmune response to sperm in vasectomy. 2011, 108 (18):7511-6 Proc. Natl. Acad. Sci. U.S.A.
1091-6490
21502500
10.1073/pnas.1017615108
http://hdl.handle.net/10033/200329
Proceedings of the National Academy of Sciences of the United States of America
en
oai:repository.helmholtz-hzi.de:10033/2012532019-08-30T11:36:32Zcom_10033_56876col_10033_56896
CD4+CD25+ regulatory T cells control CD8+ T-cell effector differentiation by modulating IL-2 homeostasis.
McNally, Alice
Hill, Geoffrey R
Sparwasser, Tim
Thomas, Ranjeny
Steptoe, Raymond J
University of Queensland Diamantina Institute, University of Queensland, Brisbane 4072, Australia.
Adaptive Immunity
Analysis of Variance
Animals
Antibodies, Monoclonal
CD8-Positive T-Lymphocytes
Cell Differentiation
Enzyme-Linked Immunosorbent Assay
Flow Cytometry
Homeostasis
Interleukin-2
Mice
Mice, Inbred C57BL
Mice, Transgenic
T-Lymphocytes, Regulatory
CD4(+)CD25(+) regulatory T cells (Treg) play a crucial role in the regulation of immune responses. Although many mechanisms of Treg suppression in vitro have been described, the mechanisms by which Treg modulate CD8(+) T cell differentiation and effector function in vivo are more poorly defined. It has been proposed, in many instances, that modulation of cytokine homeostasis could be an important mechanism by which Treg regulate adaptive immunity; however, direct experimental evidence is sparse. Here we demonstrate that CD4(+)CD25(+) Treg, by critically regulating IL-2 homeostasis, modulate CD8(+) T-cell effector differentiation. Expansion and effector differentiation of CD8(+) T cells is promoted by autocrine IL-2 but, by competing for IL-2, Treg limit CD8(+) effector differentiation. Furthermore, a regulatory loop exists between Treg and CD8(+) effector T cells, where IL-2 produced during CD8(+) T-cell effector differentiation promotes Treg expansion.
2012-01-10T13:39:01Z
2012-01-10T13:39:01Z
2011-05-03
Article
CD4+CD25+ regulatory T cells control CD8+ T-cell effector differentiation by modulating IL-2 homeostasis. 2011, 108 (18):7529-34 Proc. Natl. Acad. Sci. U.S.A.
1091-6490
21502514
10.1073/pnas.1103782108
http://hdl.handle.net/10033/201253
Proceedings of the National Academy of Sciences of the United States of America
en
oai:repository.helmholtz-hzi.de:10033/2033092019-08-30T11:26:13Zcom_10033_56876col_10033_56896
Virus-induced tumor inflammation facilitates effective DC cancer immunotherapy in a Treg-dependent manner in mice.
Woller, Norman
Knocke, Sarah
Mundt, Bettina
Gürlevik, Engin
Strüver, Nina
Kloos, Arnold
Boozari, Bita
Schache, Peter
Manns, Michael P
Malek, Nisar P
Sparwasser, Tim
Zender, Lars
Wirth, Thomas C
Kubicka, Stefan
Kühnel, Florian
Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
Animals
Cancer Vaccines
Cell Line
Dendritic Cells
Humans
Immunotherapy
Mice
Mice, Inbred Strains
Neoplasms
Neoplasms, Experimental
T-Lymphocytes, Regulatory
Viruses
Vaccination using DCs pulsed with tumor lysates or specific tumor-associated peptides has so far yielded limited clinical success for cancer treatment, due mainly to the low immunogenicity of tumor-associated antigens. In this study, we have identified intratumoral virus-induced inflammation as a precondition for effective antitumor DC vaccination in mice. Administration of a tumor-targeted DC vaccine during ongoing virus-induced tumor inflammation, a regimen referred to as oncolysis-assisted DC vaccination (ODC), elicited potent antitumoral CD8+ T cell responses. This potent effect was not replicated by TLR activation outside the context of viral infection. ODC-elicited immune responses mediated marked tumor regression and successful eradication of preestablished lung colonies, an essential prerequisite for potentially treating metastatic cancers. Unexpectedly, depletion of Tregs during ODC did not enhance therapeutic efficacy; rather, it abrogated antitumor cytotoxicity. This phenomenon could be attributed to a compensatory induction of myeloid-derived suppressor cells in Treg-depleted and thus vigorously inflamed tumors, which prevented ODC-mediated immune responses. Consequently, Tregs are not only general suppressors of immune responses, but are essential for the therapeutic success of multimodal and temporally fine-adjusted vaccination strategies. Our results highlight tumor-targeting, replication-competent viruses as attractive tools for eliciting effective antitumor responses upon DC vaccination.
2012-01-16T14:40:13Z
2012-01-16T14:40:13Z
2011-07-01
Article
Virus-induced tumor inflammation facilitates effective DC cancer immunotherapy in a Treg-dependent manner in mice. 2011, 121 (7):2570-82 J. Clin. Invest.
1558-8238
21646722
10.1172/JCI45585
http://hdl.handle.net/10033/203309
The Journal of clinical investigation
en
oai:repository.helmholtz-hzi.de:10033/2037492019-08-30T11:31:49Zcom_10033_56876col_10033_56896
The adjuvant effect of TLR agonists on CD4(+) effector T cells is under the indirect control of regulatory T cells.
Olivier, Aurélie
Sainz-Perez, Alexander
Dong, Hui
Sparwasser, Tim
Majlessi, Laleh
Leclerc, Claude
Department of Immunology, Paris, France.
Adjuvants, Immunologic
Amino Acid Sequence
Animals
CD4-Positive T-Lymphocytes
Female
Flow Cytometry
Forkhead Transcription Factors
Gene Expression Profiling
Green Fluorescent Proteins
Imidazoles
Lipopolysaccharides
Lymphocyte Activation
Mice
Mice, Inbred C57BL
Mice, Knockout
Mice, Transgenic
Molecular Sequence Data
Oligodeoxyribonucleotides
Ovalbumin
Peptide Fragments
Poly I-C
Reverse Transcriptase Polymerase Chain Reaction
T-Lymphocytes, Regulatory
Toll-Like Receptors
Zymosan
TLR agonists have been suggested to directly impact Tregs, thereby enhancing or reversing their suppressive function. Here, in order to select TLR agonists leading to potent effector T-cell responses, while minimizing Treg inhibitory function, we used a model antigen, covalently linked to an inert delivery system, combined with a large panel of TLR agonists, for the immunization of mice with an attenuated/depleted or intact Treg subset. We observed that the negative modulation of effector CD4(+) T cells exerted by Tregs cannot be circumvented, whatever the TLR agonist used as adjuvant. To better understand the impact of TLR agonists on Tregs, we investigated (i) the TLR expression profile of highly purified CD4(+) Foxp3(+) Tregs, at steady state or subsequent to in vivo activation by TLR agonists and (ii) the Treg phenotype after in vivo and in vitro activation by TLR agonists. Our results demonstrate that TLR agonists, as single signal inducers, are not able to directly activate Tregs. The phenotypic Treg activation observed in vivo, following TLR administration, does not result from cross-talk with conventional T cells but is rather a consequence of the interaction with other immune cell type(s).
2012-01-19T15:03:59Z
2012-01-19T15:03:59Z
2011-08
Article
The adjuvant effect of TLR agonists on CD4(+) effector T cells is under the indirect control of regulatory T cells. 2011, 41 (8):2303-13 Eur. J. Immunol.
1521-4141
21538349
10.1002/eji.201041387
http://hdl.handle.net/10033/203749
European journal of immunology
en
oai:repository.helmholtz-hzi.de:10033/2370512019-08-30T11:30:54Zcom_10033_56876col_10033_56896
Lack of Foxp3+ macrophages in both untreated and B16 melanoma-bearing mice.
Mayer, Christian T
Kühl, Anja A
Loddenkemper, Christoph
Sparwasser, Tim
Animals
Antigens, CD11
Cell Count
Down-Regulation
Flow Cytometry
Fluorescent Antibody Technique
Forkhead Transcription Factors
Macrophages
Male
Melanoma, Experimental
Mice
Mice, Transgenic
Skin Neoplasms
2012-08-02T12:18:59Z
2012-08-02T12:18:59Z
2012-02-02
Article
Lack of Foxp3+ macrophages in both untreated and B16 melanoma-bearing mice. 2012, 119 (5):1314-5 Blood
1528-0020
22308282
10.1182/blood-2011-11-392266
http://hdl.handle.net/10033/237051
Blood
en
Archived with thanks to Blood
oai:repository.helmholtz-hzi.de:10033/2405712019-08-30T11:37:24Zcom_10033_56876col_10033_56896
Langerhans cells protect from allergic contact dermatitis in mice by tolerizing CD8(+) T cells and activating Foxp3(+) regulatory T cells.
Gomez de Agüero, Mercedes
Vocanson, Marc
Hacini-Rachinel, Fériel
Taillardet, Morgan
Sparwasser, Tim
Kissenpfennig, Adrien
Malissen, Bernard
Kaiserlian, Dominique
Dubois, Bertrand
INSERM, U851, Lyon, France.
Allergens
Animals
Antigen Presentation
Antigens, CD
CD8-Positive T-Lymphocytes
Cell Communication
Cell Movement
Cells, Cultured
Dermatitis, Allergic Contact
Dinitrobenzenes
Epidermis
Forkhead Transcription Factors
Immune Tolerance
Inducible T-Cell Co-Stimulator Protein
Langerhans Cells
Lymph Nodes
Lymphocyte Activation
Mice
Mice, Inbred C57BL
Mice, Transgenic
T-Lymphocytes, Regulatory
Allergic contact dermatitis is the most frequent occupational disease in industrialized countries. It is caused by CD8(+) T cell-mediated contact hypersensitivity (CHS) reactions triggered at the site of contact by a variety of chemicals, also known as weak haptens, present in fragrances, dyes, metals, preservatives, and drugs. Despite the myriad of potentially allergenic substances that can penetrate the skin, sensitization is relatively rare and immune tolerance to the substance is often induced by as yet poorly understood mechanisms. Here we show, using the innocuous chemical 2,4-dinitrothiocyanobenzene (DNTB), that cutaneous immune tolerance in mice critically depends on epidermal Langerhans cells (LCs), which capture DNTB and migrate to lymph nodes for direct presentation to CD8(+) T cells. Depletion and adoptive transfer experiments revealed that LCs conferred protection from development of CHS by a mechanism involving both anergy and deletion of allergen-specific CD8(+) T cells and activation of a population of T cells identified as ICOS(+)CD4(+)Foxp3(+) Tregs. Our findings highlight the critical role of LCs in tolerance induction in mice to the prototype innocuous hapten DNTB and suggest that strategies targeting LCs might be valuable for prevention of cutaneous allergy.
2012-08-30T08:49:33Z
2012-08-30T08:49:33Z
2012-05-01
Article
Langerhans cells protect from allergic contact dermatitis in mice by tolerizing CD8(+) T cells and activating Foxp3(+) regulatory T cells. 2012, 122 (5):1700-11 J. Clin. Invest.
1558-8238
22523067
10.1172/JCI59725
http://hdl.handle.net/10033/240571
The Journal of clinical investigation
en
Archived with thanks to The Journal of clinical investigation
oai:repository.helmholtz-hzi.de:10033/2483552019-08-30T11:28:23Zcom_10033_56876col_10033_56896
Vagaries of fluorochrome reporter gene expression in Foxp3+ regulatory T cells.
Schallenberg, Sonja
Petzold, Cathleen
Tsai, Pei-Yun
Sparwasser, Tim
Kretschmer, Karsten
Immunotolerance in Regeneration, CRTD/DFG-Center for Regenerative Therapies Dresden, Technical University Dresden, Dresden, Germany.
CD4(+)CD25(+) regulatory T (Treg) cell lineage commitment and expression of the transcription factor Foxp3 can be induced at the CD4(+)CD8(+) double-positive (DP) and CD4(+)CD8(?) single-positive stages of thymic development, as well as in postthymic CD4(+) T cells in peripheral lymphoid tissues. The availability of transgenic mice with Foxp3-dependent fluorochrome reporter gene expression has greatly facilitated studies on the intra- and extrathymic generation of murine Foxp3(+) Treg cells. Here, we performed a comparative analysis of thymic Treg cell development and peripheral compartments of mature Treg cells in various transgenic strains with gene targeted and bacterial artificial chromosome (BAC)-driven Foxp3-fluorochrome expression. These studies revealed a relative deficiency of Foxp3(+) DP thymocytes selectively in mice with targeted insertion of the fluorochrome reporter gene coding sequence into the endogenous Foxp3 gene. While Foxp3 BAC-driven fluorochrome expression in ex vivo CD4(+) T cells was found to faithfully reflect Foxp3 protein expression, we provide evidence that Foxp3 BAC transgenesis can result in sizable populations of Foxp3(+) Treg cells that lack fluorochrome reporter expression. This could be attributed to both timely delayed up-regulation of BAC expression in developing Treg cells and the accumulation of peripheral Foxp3(+) Treg cells with continuous transcriptional inactivity of the Foxp3 BAC transgene.
2012-10-11T10:41:14Z
2012-10-11T10:41:14Z
2012
Article
Vagaries of fluorochrome reporter gene expression in Foxp3+ regulatory T cells. 2012, 7 (8):e41971 PLoS ONE
1932-6203
22879902
10.1371/journal.pone.0041971
http://hdl.handle.net/10033/248355
PloS one
en
Archived with thanks to PloS one
oai:repository.helmholtz-hzi.de:10033/2541522019-08-30T11:28:23Zcom_10033_56876col_10033_56896
Absence of Foxp3(+) Regulatory T Cells during Allergen Provocation Does Not Exacerbate Murine Allergic Airway Inflammation.
Baru, Abdul Mannan
Ganesh, Venkateswaran
Krishnaswamy, Jayendra Kumar
Hesse, Christina
Untucht, Christopher
Glage, Silke
Behrens, Georg
Mayer, Christian Thomas
Puttur, Franz
Sparwasser, Tim
Institute of Infection Immunology, TWINCORE, Centre for Experimental and Clinical Infection Research; a joint venture between the Medical School Hannover (MHH) and the Helmholtz Centre for Infection Research (HZI), Hannover, Germany.
Regulatory T cells (Tregs) play a non-redundant role in maintenance of immune homeostasis. This is achieved by suppressing both, priming of naïve cells and effector cell functions. Although Tregs have been implicated in modulating allergic immune responses, their influence on distinct phases of development of allergies remains unclear. In this study, by using bacterial artificial chromosome (BAC)-transgenic Foxp3-DTR (DEREG) mice we demonstrate that the absence of Foxp3(+) Tregs during the allergen challenge surprisingly does not exacerbate allergic airway inflammation in BALB/c mice. As genetic disposition due to strain specificity may contribute significantly to development of allergies, we performed similar experiment in C57BL/6 mice, which are less susceptible to allergy in the model of sensitization used in this study. We report that the genetic background does not influence the consequence of this depletion regimen. These results signify the temporal regulation exerted by Foxp3(+) Tregs in limiting allergic airway inflammation and may influence their application as potential therapeutics.
2012-11-30T17:13:22Z
2012-11-30T17:13:22Z
2012
Article
Absence of Foxp3(+) Regulatory T Cells during Allergen Provocation Does Not Exacerbate Murine Allergic Airway Inflammation. 2012, 7 (10):e47102 PLoS ONE
1932-6203
23071726
10.1371/journal.pone.0047102
http://hdl.handle.net/10033/254152
PloS one
en
Archived with thanks to PloS one
oai:repository.helmholtz-hzi.de:10033/2549292019-08-30T11:28:51Zcom_10033_56876col_10033_56896
Schistosomes induce regulatory features in human and mouse CD1d(hi) B cells: inhibition of allergic inflammation by IL-10 and regulatory T cells.
van der Vlugt, Luciën E P M
Labuda, Lucja A
Ozir-Fazalalikhan, Arifa
Lievers, Ellen
Gloudemans, Anouk K
Liu, Kit-Yeng
Barr, Tom A
Sparwasser, Tim
Boon, Louis
Ngoa, Ulysse Ateba
Feugap, Eliane Ngoune
Adegnika, Ayola A
Kremsner, Peter G
Gray, David
Yazdanbakhsh, Maria
Smits, Hermelijn H
Department of Parasitology, Leiden University Medical Center, Leiden, The Netherlands.
Animals
Antigens, CD1d
B-Lymphocytes
Child
Gabon
Helminths
Humans
Hypersensitivity
Inflammation
Interleukin-10
Mice
Mice, Knockout
Schistosoma
T-Lymphocytes, Regulatory
Chronic helminth infections, such as schistosomes, are negatively associated with allergic disorders. Here, using B cell IL-10-deficient mice, Schistosoma mansoni-mediated protection against experimental ovalbumin-induced allergic airway inflammation (AAI) was shown to be specifically dependent on IL-10-producing B cells. To study the organs involved, we transferred B cells from lungs, mesenteric lymph nodes or spleen of OVA-infected mice to recipient OVA-sensitized mice, and showed that both lung and splenic B cells reduced AAI, but only splenic B cells in an IL-10-dependent manner. Although splenic B cell protection was accompanied by elevated levels of pulmonary FoxP3(+) regulatory T cells, in vivo ablation of FoxP3(+) T cells only moderately restored AAI, indicating an important role for the direct suppressory effect of regulatory B cells. Splenic marginal zone CD1d(+) B cells proved to be the responsible splenic B cell subset as they produced high levels of IL-10 and induced FoxP3(+) T cells in vitro. Indeed, transfer of CD1d(+) MZ-depleted splenic B cells from infected mice restored AAI. Markedly, we found a similarly elevated population of CD1d(hi) B cells in peripheral blood of Schistosoma haematobium-infected Gabonese children compared to uninfected children and these cells produced elevated levels of IL-10. Importantly, the number of IL-10-producing CD1d(hi) B cells was reduced after anti-schistosome treatment. This study points out that in both mice and men schistosomes have the capacity to drive the development of IL-10-producing regulatory CD1d(hi) B cells and furthermore, these are instrumental in reducing experimental allergic inflammation in mice.
2012-12-07T15:29:08Z
2012-12-07T15:29:08Z
2012
Article
Schistosomes induce regulatory features in human and mouse CD1d(hi) B cells: inhibition of allergic inflammation by IL-10 and regulatory T cells. 2012, 7 (2):e30883 PLoS ONE
1932-6203
22347409
10.1371/journal.pone.0030883
http://hdl.handle.net/10033/254929
PloS one
en
Archived with thanks to PloS one
oai:repository.helmholtz-hzi.de:10033/2564932019-08-30T11:28:51Zcom_10033_56876col_10033_56896
Regulatory T cells increase the avidity of primary CD8+ T cell responses and promote memory.
Pace, Luigia
Tempez, Andy
Arnold-Schrauf, Catharina
Lemaitre, Fabrice
Bousso, Philippe
Fetler, Luc
Sparwasser, Tim
Amigorena, Sebastian
INSERM U932, Immunity and Cancer, Institut Curie, F-75248 Paris Cedex 05, France.
Animals
CD8-Positive T-Lymphocytes
Chemokine CCL1
Chemokine CCL4
Chemokine CCL5
Female
Immunity, Cellular
Immunologic Memory
Listeria monocytogenes
Listeriosis
Lymphocyte Depletion
Mice
Mice, Inbred C57BL
Proteins
T-Lymphocytes, Regulatory
Although regulatory T cells (T(regs)) are known to suppress self-reactive autoimmune responses, their role during T cell responses to nonself antigens is not well understood. We show that T(regs) play a critical role during the priming of immune responses in mice. T(reg) depletion induced the activation and expansion of a population of low-avidity CD8(+) T cells because of overproduction of CCL-3/4/5 chemokines, which stabilized the interactions between antigen-presenting dendritic cells and low-avidity T cells. In the absence of T(regs), the avidity of the primary immune response was impaired, which resulted in reduced memory to Listeria monocytogenes. These results suggest that T(regs) are important regulators of the homeostasis of CD8(+) T cell priming and play a critical role in the induction of high-avidity primary responses and effective memory.
2012-12-12T14:07:20Z
2012-12-12T14:07:20Z
2012-10-26
Article
Regulatory T cells increase the avidity of primary CD8+ T cell responses and promote memory. 2012, 338 (6106):532-6 Science
1095-9203
23112334
10.1126/science.1227049
http://hdl.handle.net/10033/256493
Science (New York, N.Y.)
en
Archived with thanks to Science (New York, N.Y.)
oai:repository.helmholtz-hzi.de:10033/2676922019-08-30T11:33:29Zcom_10033_56876col_10033_56896
IκB(NS) Protein Mediates Regulatory T Cell Development via Induction of the Foxp3 Transcription Factor.
Schuster, Marc
Glauben, Rainer
Plaza-Sirvent, Carlos
Schreiber, Lisa
Annemann, Michaela
Floess, Stefan
Kühl, Anja A
Clayton, Linda K
Sparwasser, Tim
Schulze-Osthoff, Klaus
Pfeffer, Klaus
Huehn, Jochen
Siegmund, Britta
Schmitz, Ingo
Systems-oriented Immunology and Inflammation Research, Helmholtz Center for Infection Research, 38124 Braunschweig, Germany, and Institute for Molecular and Clinical Immunology, Otto-von-Guericke University, 39120 Magdeburg, Germany.
Forkhead box P3 positive (Foxp3(+)) regulatory T (Treg) cells suppress immune responses and regulate peripheral tolerance. Here we show that the atypical inhibitor of NFκB (IκB) IκB(NS) drives Foxp3 expression via association with the promoter and the conserved noncoding sequence 3 (CNS3) of the Foxp3 locus. Consequently, IκB(NS) deficiency leads to a substantial reduction of Foxp3(+) Treg cells in vivo and impaired Foxp3 induction upon transforming growth factor-β (TGF-β) treatment in vitro. Moreover, fewer Foxp3(+) Treg cells developed from IκB(NS)-deficient CD25(-)CD4(+) T cells adoptively transferred into immunodeficient recipients. Importantly, IκB(NS) was required for the transition of immature GITR(+)CD25(+)Foxp3(-) thymic Treg cell precursors into Foxp3(+) cells. In contrast to mice lacking c-Rel or Carma1, IκB(NS)-deficient mice do not show reduced Treg precursor cells. Our results demonstrate that IκB(NS) critically regulates Treg cell development in the thymus and during gut inflammation, indicating that strategies targeting IκB(NS) could modulate the Treg cell compartment.
2013-01-30T14:02:36Z
2013-01-30T14:02:36Z
2012-12-14
Article
IκB(NS) Protein Mediates Regulatory T Cell Development via Induction of the Foxp3 Transcription Factor. 2012, 37 (6):998-1008 Immunity
1097-4180
23200824
10.1016/j.immuni.2012.08.023
http://hdl.handle.net/10033/267692
Immunity
en
Archived with thanks to Immunity
oai:repository.helmholtz-hzi.de:10033/2688922019-08-30T11:33:57Zcom_10033_56876col_10033_56896
T cell receptor stimulation-induced epigenetic changes and Foxp3 expression are independent and complementary events required for Treg cell development.
Ohkura, Naganari
Hamaguchi, Masahide
Morikawa, Hiromasa
Sugimura, Kyoko
Tanaka, Atsushi
Ito, Yoshinaga
Osaki, Motonao
Tanaka, Yoshiaki
Yamashita, Riu
Nakano, Naoko
Huehn, Jochen
Fehling, Hans Joerg
Sparwasser, Tim
Nakai, Kenta
Sakaguchi, Shimon
Department of Experimental Immunology, World Premier International Immunology Frontier Research Center, Osaka University, Suita, Japan.
Animals
DNA Methylation
Epigenesis, Genetic
Forkhead Transcription Factors
Gene Expression
Histones
Male
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Receptors, Antigen, T-Cell
T-Lymphocytes, Regulatory
Thymus Gland
The transcription factor Foxp3 is essential for the development of regulatory T (Treg) cells, yet its expression is insufficient for establishing the Treg cell lineage. Here we showed that Treg cell development was achieved by the combination of two independent processes, i.e., the expression of Foxp3 and the establishment of Treg cell-specific CpG hypomethylation pattern. Both events were induced by T cell receptor stimulation. The Treg cell-type CpG hypomethylation began in the thymus and continued to proceed in the periphery and could be fully established without Foxp3. The hypomethylation was required for Foxp3(+) T cells to acquire Treg cell-type gene expression, lineage stability, and full suppressive activity. Thus, those T cells in which the two events have concurrently occurred are developmentally set into the Treg cell lineage. This model explains how Treg cell fate and plasticity is controlled and can be exploited to generate functionally stable Treg cells.
2013-02-11T10:31:47Z
2013-02-11T10:31:47Z
2012-11-16
Article
T cell receptor stimulation-induced epigenetic changes and Foxp3 expression are independent and complementary events required for Treg cell development. 2012, 37 (5):785-99 Immunity
1097-4180
23123060
10.1016/j.immuni.2012.09.010
http://hdl.handle.net/10033/268892
Immunity
en
Archived with thanks to Immunity
oai:repository.helmholtz-hzi.de:10033/2699362019-08-30T11:31:49Zcom_10033_56876col_10033_56896
Neuropilin 1 deficiency on CD4+Foxp3+ regulatory T cells impairs mouse melanoma growth.
Hansen, Wiebke
Hutzler, Marina
Abel, Simone
Alter, Christina
Stockmann, Christian
Kliche, Stefanie
Albert, Juliane
Sparwasser, Tim
Sakaguchi, Shimon
Westendorf, Astrid M
Schadendorf, Dirk
Buer, Jan
Helfrich, Iris
Institute of Medical Microbiology, University Hospital Essen, University Duisburg-Essen, 45122 Essen, Germany. wiebke.hansen@uk-essen.de
Animals
CD4-Positive T-Lymphocytes
CD8-Positive T-Lymphocytes
Cell Line, Tumor
Cell Movement
Flow Cytometry
Forkhead Transcription Factors
Gene Expression Regulation, Neoplastic
Humans
Immunohistochemistry
Lymphocyte Activation
Melanoma, Experimental
Mice
Mice, Inbred C57BL
Mice, Knockout
Mice, Transgenic
Neuropilin-1
Reverse Transcriptase Polymerase Chain Reaction
Skin Neoplasms
T-Lymphocytes, Regulatory
Tumor Burden
Tumor Escape
Vascular Endothelial Growth Factor A
Infiltration of Foxp3(+) regulatory T (T reg) cells is considered to be a critical step during tumor development and progression. T reg cells supposedly suppress locally an effective anti-tumor immune response within tumor tissues, although the precise mechanism by which T reg cells infiltrate the tumor is still unclear. We provide evidence that Neuropilin 1 (Nrp-1), highly expressed by Foxp3(+) T reg cells, regulates the immunological anti-tumor control by guiding T reg cells into the tumor in response to tumor-derived vascular endothelial growth factor (VEGF). We demonstrate for the first time that T cell-specific ablation of Nrp-1 expression results in a significant breakdown in tumor immune escape in various transplantation models and in a spontaneous, endogenously driven melanoma model associated with strongly reduced tumor growth and prolonged tumor-free survival. Strikingly, numbers of tumor-infiltrating Foxp3(+) T reg cells were significantly reduced accompanied by enhanced activation of CD8(+) T cells within tumors of T cell-specific Nrp-1-deficient mice. This phenotype can be reversed by adoptive transfer of Nrp-1(+) T reg cells from wild-type mice. Thus, our data strongly suggest that Nrp-1 acts as a key mediator of Foxp3(+) T reg cell infiltration into the tumor site resulting in a dampened anti-tumor immune response and enhanced tumor progression.
2013-02-21T10:26:55Z
2013-02-21T10:26:55Z
2012-10-22
Article
Neuropilin 1 deficiency on CD4+Foxp3+ regulatory T cells impairs mouse melanoma growth. 2012, 209 (11):2001-16 J. Exp. Med.
1540-9538
23045606
10.1084/jem.20111497
http://hdl.handle.net/10033/269936
The Journal of experimental medicine
en
Archived with thanks to The Journal of experimental medicine
oai:repository.helmholtz-hzi.de:10033/2711942019-08-30T11:25:43Zcom_10033_56876col_10033_56896
A novel bacterial artificial chromosome-transgenic podoplanin-cre mouse targets lymphoid organ stromal cells in vivo.
Onder, Lucas
Scandella, Elke
Chai, Qian
Firner, Sonja
Mayer, Christian T
Sparwasser, Tim
Thiel, Volker
Rülicke, Thomas
Ludewig, Burkhard
Institute of Immunobiology, Cantonal Hospital St. Gallen St. Gallen, Switzerland.
Stromal cells provide the structural foundation of secondary lymphoid organs (SLOs), and regulate leukocyte access and cell migration within the different compartments of spleen and lymph nodes (LNs). Furthermore, several stromal cell subsets have been implied in shaping of T cell responses through direct presentation of antigen. Despite significant gain of knowledge on the biology of different SLO-resident stromal cell subsets, their molecular and functional characterization has remained incomplete. To address this need, we have generated a bacterial artificial chromosome-transgenic mouse model that utilizes the podoplanin (pdpn) promoter to express the Cre-recombinase exclusively in stromal cells of SLOs. The characterization of the Pdpn-Cre mouse revealed transgene expression in subsets of fibroblastic reticular cells and lymphatic endothelial cells in LNs. Furthermore, the transgene facilitated the identification of a novel splenic perivascular stromal cell subpopulation that forms web-like structures around central arterioles. Assessment of the in vivo antigen expression in the genetically tagged stromal cells in Pdpn-Cre mice revealed activation of both MHC I and II-restricted TCR transgenic T cells. Taken together, stromal pdpn-Cre expression is well-suited to characterize the phenotype and to dissect the function of lymphoid organ stromal cells.
2013-03-05T15:15:47Z
2013-03-05T15:15:47Z
2011
Article
A novel bacterial artificial chromosome-transgenic podoplanin-cre mouse targets lymphoid organ stromal cells in vivo. 2011, 2:50 Front Immunol
1664-3224
22566840
10.3389/fimmu.2011.00050
http://hdl.handle.net/10033/271194
Frontiers in immunology
en
Archived with thanks to Frontiers in immunology
oai:repository.helmholtz-hzi.de:10033/2717052019-08-30T11:28:23Zcom_10033_56876col_10033_56896
Tumor-specific CD4(+) T cells develop cytotoxic activity and eliminate virus-induced tumor cells in the absence of regulatory T cells.
Akhmetzyanova, Ilseyar
Zelinskyy, Gennadiy
Schimmer, Simone
Brandau, Sven
Altenhoff, Petra
Sparwasser, Tim
Dittmer, Ulf
Institute for Virology, University of Duisburg-Essen, Virchowstr 179, 45147, Essen, Germany, ilseyar.akhmetzyanova@uni-due.de.
The important role of tumor-specific cytotoxic CD8(+) T cells is well defined in the immune control of the tumors, but the role of effector CD4(+) T cells is poorly understood. In the current research, we have used a murine retrovirus-induced tumor cell line of C57BL/6 mouse origin, namely FBL-3 cells, as a model to study basic mechanisms of immunological control and escape during tumor formation. This study shows that tumor-specific CD4(+) T cells are able to protect against virus-induced tumor cells. We show here that there is an expansion of tumor-specific CD4(+) T cells producing cytokines and cytotoxic molecule granzyme B (GzmB) in the early phase of tumor growth. Importantly, we demonstrate that in vivo depletion of regulatory T cells (Tregs) and CD8(+) T cells in FBL-3-bearing DEREG transgenic mice augments IL-2 and GzmB production by CD4(+) T cells and increases FV-specific CD4(+) T-cell effector and cytotoxic responses leading to the complete tumor regression. Therefore, the capacity to reject tumor acquired by tumor-reactive CD4(+) T cells largely depends on the direct suppressive activity of Tregs. We suggest that a cytotoxic CD4(+) T-cell immune response may be induced to enhance resistance against oncovirus-associated tumors.
2013-03-11T15:15:13Z
2013-03-11T15:15:13Z
2013-02
Article
Tumor-specific CD4(+) T cells develop cytotoxic activity and eliminate virus-induced tumor cells in the absence of regulatory T cells. 2013, 62 (2):257-71 Cancer Immunol. Immunother.
1432-0851
22890822
10.1007/s00262-012-1329-y
http://hdl.handle.net/10033/271705
Cancer immunology, immunotherapy : CII
en
Archived with thanks to Cancer immunology, immunotherapy : CII
oai:repository.helmholtz-hzi.de:10033/2969852019-08-30T11:25:43Zcom_10033_56876col_10033_56896
Depletion of FOXP3+ regulatory T cells promotes hypercholesterolemia and atherosclerosis.
Klingenberg, Roland
Gerdes, Norbert
Badeau, Robert M
Gisterå, Anton
Strodthoff, Daniela
Ketelhuth, Daniel F J
Lundberg, Anna M
Rudling, Mats
Nilsson, Stefan K
Olivecrona, Gunilla
Zoller, Stefan
Lohmann, Christine
Lüscher, Thomas F
Jauhiainen, Matti
Sparwasser, Tim
Hansson, Göran K
Center for Molecular Medicine, Department of Medicine, Karolinska University Hospital, Karolinska Institute, Stockholm, Sweden.
Animals
Aorta
Atherosclerosis
Cells, Cultured
Forkhead Transcription Factors
Hypercholesterolemia
Lipase
Lipid Metabolism
Lipids
Lipoproteins, VLDL
Liver
Lymphocyte Depletion
Male
Mice
Mice, Inbred C57BL
Mice, Transgenic
Oligonucleotide Array Sequence Analysis
Phospholipid Transfer Proteins
Receptors, LDL
T-Lymphocytes, Regulatory
Transcriptome
Atherosclerosis is a chronic inflammatory disease promoted by hyperlipidemia. Several studies support FOXP3-positive regulatory T cells (Tregs) as inhibitors of atherosclerosis; however, the mechanism underlying this protection remains elusive. To define the role of FOXP3-expressing Tregs in atherosclerosis, we used the DEREG mouse, which expresses the diphtheria toxin (DT) receptor under control of the Treg-specific Foxp3 promoter, allowing for specific ablation of FOXP3+ Tregs. Lethally irradiated, atherosclerosis-prone, low-density lipoprotein receptor-deficient (Ldlr(-/-)) mice received DEREG bone marrow and were injected with DT to eliminate FOXP3(+) Tregs. Depletion of Tregs caused a 2.1-fold increase in atherosclerosis without a concomitant increase in vascular inflammation. These mice also exhibited a 1.7-fold increase in plasma cholesterol and an atherogenic lipoprotein profile with increased levels of VLDL. Clearance of VLDL and chylomicron remnants was hampered, leading to accumulation of cholesterol-rich particles in the circulation. Functional and protein analyses complemented by gene expression array identified reduced protein expression of sortilin-1 in liver and increased plasma enzyme activity of lipoprotein lipase, hepatic lipase, and phospholipid transfer protein as mediators of the altered lipid phenotype. These results demonstrate that FOXP3(+) Tregs inhibit atherosclerosis by modulating lipoprotein metabolism.
2013-07-24T14:44:31Z
2013-07-24T14:44:31Z
2013-03-01
Article
Depletion of FOXP3+ regulatory T cells promotes hypercholesterolemia and atherosclerosis. 2013, 123 (3):1323-34 J. Clin. Invest.
1558-8238
23426179
10.1172/JCI63891
http://hdl.handle.net/10033/296985
The Journal of clinical investigation
en
Archived with thanks to The Journal of clinical investigation
oai:repository.helmholtz-hzi.de:10033/3054422019-08-30T11:37:23Zcom_10033_56876col_10033_56896
IL-21 restricts virus-driven Treg cell expansion in chronic LCMV infection.
Schmitz, Iwana
Schneider, Christoph
Fröhlich, Anja
Frebel, Helge
Christ, Daniel
Leonard, Warren J
Sparwasser, Tim
Oxenius, Annette
Freigang, Stefan
Kopf, Manfred
Molecular Biomedicine, Institute of Molecular Health Sciences, Department of Biology, ETH Zurich, Zurich, Switzerland.
Foxp3+ regulatory T (Treg) cells are essential for the maintenance of immune homeostasis and tolerance. During viral infections, Treg cells can limit the immunopathology resulting from excessive inflammation, yet potentially inhibit effective antiviral T cell responses and promote virus persistence. We report here that the fast-replicating LCMV strain Docile triggers a massive expansion of the Treg population that directly correlates with the size of the virus inoculum and its tendency to establish a chronic, persistent infection. This Treg cell proliferation was greatly enhanced in IL-21R-/- mice and depletion of Treg cells partially rescued defective CD8+ T cell cytokine responses and improved viral clearance in some but not all organs. Notably, IL-21 inhibited Treg cell expansion in a cell intrinsic manner. Moreover, experimental augmentation of Treg cells driven by injection of IL-2/anti-IL-2 immune complexes drastically impaired the functionality of the antiviral T cell response and impeded virus clearance. As a consequence, mice became highly susceptible to chronic infection following exposure to low virus doses. These findings reveal virus-driven Treg cell proliferation as potential evasion strategy that facilitates T cell exhaustion and virus persistence. Furthermore, they suggest that besides its primary function as a direct survival signal for antiviral CD8+ T cells during chronic infections, IL-21 may also indirectly promote CD8+ T cell poly-functionality by restricting the suppressive activity of infection-induced Treg cells.
2013-11-15T14:37:38Z
2013-11-15T14:37:38Z
2013-05
Article
IL-21 restricts virus-driven Treg cell expansion in chronic LCMV infection. 2013, 9 (5):e1003362 PLoS Pathog.
1553-7374
23696736
10.1371/journal.ppat.1003362
http://hdl.handle.net/10033/305442
PLoS pathogens
en
Archived with thanks to PLoS pathogens
oai:repository.helmholtz-hzi.de:10033/3051992019-08-30T11:37:23Zcom_10033_56876col_10033_56896
Regulatory CD4+Foxp3+ T cells control the severity of anaphylaxis.
Kanjarawi, Reem
Dy, Michel
Bardel, Emilie
Sparwasser, Tim
Dubois, Bertrand
Mecheri, Salah
Kaiserlian, Dominique
CIRI, International Center for Infectiology Research, Mucosal immunity, Vaccination & Biotherapies Team, Université de Lyon, Lyon, France.
Anaphylaxis is a life-threatening outcome of immediate-type hypersensitivity to allergen, consecutive to mast cell degranulation by allergen-specific IgE. Regulatory T cells (Treg) can control allergic sensitization and mast cell degranulation, yet their clinical benefit on anaphylactic symptoms is poorly documented. Here we investigated whether Treg action during the effector arm of the allergic response alleviates anaphylaxis.
2013-11-11T15:14:32Z
2013-11-11T15:14:32Z
2013
Article
Regulatory CD4+Foxp3+ T cells control the severity of anaphylaxis. 2013, 8 (7):e69183 PLoS ONE
1932-6203
23922690
10.1371/journal.pone.0069183
http://hdl.handle.net/10033/305199
PloS one
en
Archived with thanks to PloS one
oai:repository.helmholtz-hzi.de:10033/3052092019-08-30T11:37:24Zcom_10033_56876col_10033_56896
Loss of the TGFβ-Activating Integrin αvβ8 on Dendritic Cells Protects Mice from Chronic Intestinal Parasitic Infection via Control of Type 2 Immunity.
Worthington, John J
Klementowicz, Joanna E
Rahman, Sayema
Czajkowska, Beata I
Smedley, Catherine
Waldmann, Herman
Sparwasser, Tim
Grencis, Richard K
Travis, Mark A
Manchester Immunology Group, Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom ; Wellcome Trust Centre for Cell-Matrix Research, Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom ; Manchester Collaborative Centre for Inflammation Research, University of Manchester, Manchester, United Kingdom.
Chronic intestinal parasite infection is a major global health problem, but mechanisms that promote chronicity are poorly understood. Here we describe a novel cellular and molecular pathway involved in the development of chronic intestinal parasite infection. We show that, early during development of chronic infection with the murine intestinal parasite Trichuris muris, TGFβ signalling in CD4+ T-cells is induced and that antibody-mediated inhibition of TGFβ function results in protection from infection. Mechanistically, we find that enhanced TGFβ signalling in CD4+ T-cells during infection involves expression of the TGFβ-activating integrin αvβ8 by dendritic cells (DCs), which we have previously shown is highly expressed by a subset of DCs in the intestine. Importantly, mice lacking integrin αvβ8 on DCs were completely resistant to chronic infection with T. muris, indicating an important functional role for integrin αvβ8-mediated TGFβ activation in promoting chronic infection. Protection from infection was dependent on CD4+ T-cells, but appeared independent of Foxp3+ Tregs. Instead, mice lacking integrin αvβ8 expression on DCs displayed an early increase in production of the protective type 2 cytokine IL-13 by CD4+ T-cells, and inhibition of this increase by crossing mice to IL-4 knockout mice restored parasite infection. Our results therefore provide novel insights into how type 2 immunity is controlled in the intestine, and may help contribute to development of new therapies aimed at promoting expulsion of gut helminths.
2013-11-11T14:35:40Z
2013-11-11T14:35:40Z
2013-10
Article
Loss of the TGFβ-Activating Integrin αvβ8 on Dendritic Cells Protects Mice from Chronic Intestinal Parasitic Infection via Control of Type 2 Immunity. 2013, 9 (10):e1003675 PLoS Pathog.
1553-7374
24098124
10.1371/journal.ppat.1003675
http://hdl.handle.net/10033/305209
PLoS pathogens
en
Archived with thanks to PLoS pathogens
oai:repository.helmholtz-hzi.de:10033/3056042019-08-30T11:37:44Zcom_10033_56876col_10033_56896
In vivo targeting of human DC-SIGN drastically enhances CD8⁺ T-cell-mediated protective immunity.
Hesse, Christina
Ginter, Wiebke
Förg, Theresa
Mayer, Christian T
Baru, Abdul Mannan
Arnold-Schrauf, Catharina
Unger, Wendy W J
Kalay, Hakan
van Kooyk, Yvette
Berod, Luciana
Sparwasser, Tim
Institute of Infection Immunology, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Medical School Hannover (MHH) and the Helmholtz Centre for Infection Research (HZI), Hannover, Germany.
Vaccination is one of the oldest yet still most effective methods to prevent infectious diseases. However, eradication of intracellular pathogens and treatment of certain diseases like cancer requiring efficient cytotoxic immune responses remain a medical challenge. In mice, a successful approach to induce strong cytotoxic CD8⁺ T-cell (CTL) reactions is to target antigens to DCs using specific antibodies against surface receptors in combination with adjuvants. A major drawback for translating this strategy into one for the clinic is the lack of analogous targets in human DCs. DC-SIGN (DC-specific-ICAM3-grabbing-nonintegrin/CD209) is a C-type lectin receptor with potent endocytic capacity and a highly restricted expression on human immature DCs. Therefore, DC-SIGN represents an ideal candidate for DC targeting. Using transgenic mice that express human DC-SIGN under the control of the murine CD11c promoter (hSIGN mice), we explored the efficacy of anti-DC-SIGN antibodies to target antigens to DCs and induce protective immune responses in vivo. We show that anti-DC-SIGN antibodies conjugated to OVA induced strong and persistent antigen-specific CD4⁺ and CD8⁺ T-cell responses, which efficiently protected from infection with OVA-expressing Listeria monocytogenes. Thus, we propose DC targeting via DC-SIGN as a promising strategy for novel vaccination protocols against intracellular pathogens.
2013-11-21T09:48:03Z
2013-11-21T09:48:03Z
2013-10
Article
In vivo targeting of human DC-SIGN drastically enhances CD8⁺ T-cell-mediated protective immunity. 2013, 43 (10):2543-53 Eur. J. Immunol.
1521-4141
23784881
10.1002/eji.201343429
http://hdl.handle.net/10033/305604
European journal of immunology
en
Archived with thanks to European journal of immunology
oai:repository.helmholtz-hzi.de:10033/3058772019-08-30T11:29:16Zcom_10033_56876col_10033_56896
Schistosoma mansoni-Mediated Suppression of Allergic Airway Inflammation Requires Patency and Foxp3+ Treg Cells
Layland, Laura E.
Straubinger, Kathrin
Ritter, Manuel
Loffredo-Verde, Eva
Garn, Holger
Sparwasser, Tim
Prazeres da Costa, Clarissa
Mitre, Edward
2013-11-28T11:13:52Z
2013-11-28T11:13:52Z
2013-11-28
Article
Schistosoma mansoni-Mediated Suppression of Allergic Airway Inflammation Requires Patency and Foxp3+ Treg Cells 2013, 7 (8):e2379 PLoS Neglected Tropical Diseases
1935-2735
10.1371/journal.pntd.0002379
http://hdl.handle.net/10033/305877
PLoS neglected Tropical Diseases
http://dx.plos.org/10.1371/journal.pntd.0002379
Archived with thanks to PLoS Neglected Tropical Diseases
oai:repository.helmholtz-hzi.de:10033/3059892019-08-30T11:37:44Zcom_10033_56876col_10033_56896
Absence of Siglec-H in MCMV infection elevates interferon alpha production but does not enhance viral clearance.
Puttur, Franz
Arnold-Schrauf, Catharina
Lahl, Katharina
Solmaz, Gulhas
Lindenberg, Marc
Mayer, Christian Thomas
Gohmert, Melanie
Swallow, Maxine
van Helt, Christopher
Schmitt, Heike
Nitschke, Lars
Lambrecht, Bart N
Lang, Roland
Messerle, Martin
Sparwasser, Tim
Institute for Infection Immunology, TWINCORE, Centre for Experimental and Clinical Infection Research: A Joint Venture between the Medical School Hannover (MHH) and the Helmholtz Centre for Infection Research (HZI), Hannover, Germany.
Plasmacytoid dendritic cells (pDCs) express the I-type lectin receptor Siglec-H and produce interferon α (IFNα), a critical anti-viral cytokine during the acute phase of murine cytomegalovirus (MCMV) infection. The ligands and biological functions of Siglec-H still remain incompletely defined in vivo. Thus, we generated a novel bacterial artificial chromosome (BAC)-transgenic "pDCre" mouse which expresses Cre recombinase under the control of the Siglec-H promoter. By crossing these mice with a Rosa26 reporter strain, a representative fraction of Siglec-H⁺ pDCs is terminally labeled with red fluorescent protein (RFP). Interestingly, systemic MCMV infection of these mice causes the downregulation of Siglec-H surface expression. This decline occurs in a TLR9- and MyD88-dependent manner. To elucidate the functional role of Siglec-H during MCMV infection, we utilized a novel Siglec-H deficient mouse strain. In the absence of Siglec-H, the low infection rate of pDCs with MCMV remained unchanged, and pDC activation was still intact. Strikingly, Siglec-H deficiency induced a significant increase in serum IFNα levels following systemic MCMV infection. Although Siglec-H modulates anti-viral IFNα production, the control of viral replication was unchanged in vivo. The novel mouse models will be valuable to shed further light on pDC biology in future studies.
2013-11-29T15:52:34Z
2013-11-29T15:52:34Z
2013-09
Article
Absence of Siglec-H in MCMV infection elevates interferon alpha production but does not enhance viral clearance. 2013, 9 (9):e1003648 PLoS Pathog.
1553-7374
24086137
10.1371/journal.ppat.1003648
http://hdl.handle.net/10033/305989
PLoS pathogens
en
Archived with thanks to PLoS pathogens
oai:repository.helmholtz-hzi.de:10033/3123312019-08-30T11:30:32Zcom_10033_56876col_10033_56896
Optimal isolation of functional Foxp3+ induced regulatory T cells using DEREG mice.
Baru, Abdul Mannan
Untucht, Christopher
Ganesh, Venkateswaran
Hesse, Christina
Mayer, Christian T
Sparwasser, Tim
Animals
CD4-Positive T-Lymphocytes
Cell Proliferation
Cell Separation
Chromosomes, Artificial, Bacterial
Dendritic Cells
Female
Flow Cytometry
Forkhead Transcription Factors
Gene Expression Regulation
Genes, Reporter
Genotype
Green Fluorescent Proteins
Inflammation
Interleukin-2 Receptor alpha Subunit
Kinetics
Male
Mice
Promoter Regions, Genetic
T-Lymphocytes, Regulatory
Foxp3 reporter mice including DEREG (DEpletion of REGulatory T cells) mice have greatly helped in exploring the biology of Foxp3(+) Tregs. DEREG mice express a DTR-eGFP fusion protein under the control of a bacterial artificial chromosome (BAC)-encoded Foxp3 promoter, allowing the viable isolation and inducible depletion of Foxp3(+) Tregs. Adaptive Tregs differentiated in vitro to express Foxp3 (iTregs) are gaining high interest as potential therapeutics for inflammatory conditions such as autoimmunity, allergy and transplant rejection. However, selective isolation of Foxp3(+) iTregs with a stable phenotype still remains to be a problem, especially in the human setting. While screening for culture conditions to generate stable CD4(+)Foxp3(+) iTregs from DEREG mice, with maximum suppressive activity, we observed an unexpected dichotomy of eGFP and Foxp3 expression which is not seen in ex vivo isolated cells from DEREG mice. Further characterization of eGFP(+)Foxp3(-) cells revealed relatively lower CD25 expression and a lack of suppressive activity in vitro. Similarly, eGFP(-) cells isolated from the same cultures were not suppressive despite of a broad CD25 expression reflecting mere T cell activation. In contrast, eGFP(+)Foxp3(+) iTregs exhibited potent suppressive activity comparable to that of natural eGFP(+)Foxp3(+) Tregs, emphasizing the importance of isolating Foxp3 expressing iTregs. Interestingly, the use of plate-bound anti-CD3 and anti-CD28 or Flt3L-driven BMDC resulted in considerable resolution of the observed dichotomy. In summary, we defined culture conditions for efficient generation of eGFP(+)Foxp3(+) iTregs by use of DEREG mice. Isolation of functional Foxp3(+) iTregs using DEREG mice can also be achieved under sub-optimal conditions based on the magnitude of surface CD25 expression, in synergy with transgene encoded eGFP. Besides, the reported phenomenon may be of general interest for exploring Foxp3 gene regulation, given that Foxp3 and eGFP expression are driven from distinct Foxp3 loci and because this dichotomy preferentially occurs only under defined in vitro conditions.
2014-02-06T14:10:18Z
2014-02-06T14:10:18Z
2012
Article
Optimal isolation of functional Foxp3+ induced regulatory T cells using DEREG mice. 2012, 7 (9):e44760 PLoS ONE
1932-6203
22957107
10.1371/journal.pone.0044760
http://hdl.handle.net/10033/312331
PloS one
en
Archived with thanks to PloS one
oai:repository.helmholtz-hzi.de:10033/3173472019-08-30T11:30:58Zcom_10033_56876col_10033_56896
Foxp3⁺ regulatory T cells delay expulsion of intestinal nematodes by suppression of IL-9-driven mast cell activation in BALB/c but not in C57BL/6 mice.
Blankenhaus, Birte
Reitz, Martina
Brenz, Yannick
Eschbach, Marie-Luise
Hartmann, Wiebke
Haben, Irma
Sparwasser, Tim
Huehn, Jochen
Kühl, Anja
Feyerabend, Thorsten B
Rodewald, Hans-Reimer
Breloer, Minka
nstitute of Infection Immunology, TWINCORE, Centre for Experimental and Clinical Infection Research
Accumulating evidence suggests that IL-9-mediated immunity plays a fundamental role in control of intestinal nematode infection. Here we report a different impact of Foxp3⁺ regulatory T cells (Treg) in nematode-induced evasion of IL-9-mediated immunity in BALB/c and C57BL/6 mice. Infection with Strongyloides ratti induced Treg expansion with similar kinetics and phenotype in both strains. Strikingly, Treg depletion reduced parasite burden selectively in BALB/c but not in C57BL/6 mice. Treg function was apparent in both strains as Treg depletion increased nematode-specific humoral and cellular Th2 response in BALB/c and C57BL/6 mice to the same extent. Improved resistance in Treg-depleted BALB/c mice was accompanied by increased production of IL-9 and accelerated degranulation of mast cells. In contrast, IL-9 production was not significantly elevated and kinetics of mast cell degranulation were unaffected by Treg depletion in C57BL/6 mice. By in vivo neutralization, we demonstrate that increased IL-9 production during the first days of infection caused accelerated mast cell degranulation and rapid expulsion of S. ratti adults from the small intestine of Treg-depleted BALB/c mice. In genetically mast cell-deficient (Cpa3-Cre) BALB/c mice, Treg depletion still resulted in increased IL-9 production but resistance to S. ratti infection was lost, suggesting that IL-9-driven mast cell activation mediated accelerated expulsion of S. ratti in Treg-depleted BALB/c mice. This IL-9-driven mast cell degranulation is a central mechanism of S. ratti expulsion in both, BALB/c and C57BL/6 mice, because IL-9 injection reduced and IL-9 neutralization increased parasite burden in the presence of Treg in both strains. Therefore our results suggest that Foxp3⁺ Treg suppress sufficient IL-9 production for subsequent mast cell degranulation during S. ratti infection in a non-redundant manner in BALB/c mice, whereas additional regulatory pathways are functional in Treg-depleted C57BL/6 mice.
2014-05-23T09:54:11Z
2014-05-23T09:54:11Z
2014-02
Article
Foxp3⁺ regulatory T cells delay expulsion of intestinal nematodes by suppression of IL-9-driven mast cell activation in BALB/c but not in C57BL/6 mice. 2014, 10 (2):e1003913 PLoS Pathog.
1553-7374
24516385
10.1371/journal.ppat.1003913
http://hdl.handle.net/10033/317347
PLoS pathogens
en
Archived with thanks to PLoS pathogens
oai:repository.helmholtz-hzi.de:10033/3178182019-08-30T11:29:47Zcom_10033_56876col_10033_56896
CD4 blockade directly inhibits mouse and human CD4(+) T cell functions independent of Foxp3(+) Tregs.
Mayer, C T
Huntenburg, J
Nandan, A
Schmitt, E
Czeloth, N
Sparwasser, Tim
CD4(+) helper T cells orchestrate protective immunity against pathogens, yet can also induce undesired pathologies including allergies, transplant rejection and autoimmunity. Non-depleting CD4-specific antibodies such as clone YTS177.9 were found to promote long-lasting T cell tolerance in animal models. Thus, CD4 blockade could represent a promising therapeutic approach for human autoimmune diseases. However, the mechanisms underlying anti-CD4-induced tolerance are incompletely resolved. Particularly, multiple immune cells express CD4 including Foxp3(+) regulatory T cells (Tregs) and dendritic cells (DCs), both controlling the activation of CD4(+)Foxp3(-) helper T cells. Utilizing mixed leukocyte reactions (MLRs) reflecting physiological interactions between T cells and DCs, we report that anti-CD4 treatment inhibits CD4(+)Foxp3(-) T cell proliferation in an IL-2-independent fashion. Notably, YTS177.9 binding induces a rapid internalization of CD4 on both CD4(+)Foxp3(-) T cells and Foxp3(+) Tregs. However, no expansion or activation of immunosuppressive CD4(+)Foxp3(+) Tregs was observed following anti-CD4 treatment. Additionally, cytokine production, maturation and T cell priming capacity of DCs are not affected by anti-CD4 exposure. In line with these data, the selective ablation of Foxp3(+) Tregs from MLRs by the use of diphtheria toxin (DT)-treated bacterial artificial chromosome (BAC)-transgenic DEREG mice completely fails to abrogate the suppressive activity of multiple anti-CD4 antibodies. Instead, tolerization is associated with the defective expression of various co-stimulatory receptors including OX40 and CD30, suggesting altered signaling through the TCR complex. Consistent with our findings in mice, anti-CD4 treatment renders human CD4(+) T cells tolerant in the absence of Tregs. Thus, our results establish that anti-CD4 antibodies can directly tolerize pathogenic CD4(+)Foxp3(-) helper T cells. This has important implications for the treatment of human inflammatory diseases.
2014-06-03T14:29:57Z
2014-06-03T14:29:57Z
2013-12
Article
CD4 blockade directly inhibits mouse and human CD4(+) T cell functions independent of Foxp3(+) Tregs. 2013, 47:73-82 J. Autoimmun.
1095-9157
24055067
10.1016/j.jaut.2013.08.008
http://hdl.handle.net/10033/317818
Journal of autoimmunity
en
Archived with thanks to Journal of autoimmunity
Elsevier Science
oai:repository.helmholtz-hzi.de:10033/3227832019-08-30T11:35:13Zcom_10033_56876col_10033_56896
Layers of dendritic cell-mediated T cell tolerance, their regulation and the prevention of autoimmunity.
Mayer, Christian T
Berod, Luciana
Sparwasser, Tim
Institute of Infection Immunology, TWINCORE/Centre for Experimental and Clinical Infection Research, Feodor-Lynen-Straβe7, 30625 Hannover, Germany.
The last decades of Nobel prize-honored research have unequivocally proven a key role of dendritic cells (DCs) at controlling both T cell immunity and tolerance. A tight balance between these opposing DC functions ensures immune homeostasis and host integrity. Its perturbation could explain pathological conditions such as the attack of self tissues, chronic infections, and tumor immune evasion. While recent insights into the complex DC network help to understand the contribution of individual DC subsets to immunity, the tolerogenic functions of DCs only begin to emerge. As these consist of many different layers, the definition of a "tolerogenic DC" is subjected to variation. Moreover, the implication of DCs and DC subsets in the suppression of autoimmunity are incompletely resolved. In this review, we point out conceptual controversies and dissect the various layers of DC-mediated T cell tolerance. These layers include central tolerance, Foxp3(+) regulatory T cells (Tregs), anergy/deletion and negative feedback regulation. The mode and kinetics of antigen presentation is highlighted as an additional factor shaping tolerance. Special emphasis is given to the interaction between layers of tolerance as well as their differential regulation during inflammation. Furthermore, potential technical caveats of DC depletion models are considered. Finally, we summarize our current understanding of DC-mediated tolerance and its role for the suppression of autoimmunity. Understanding the mechanisms of DC-mediated tolerance and their complex interplay is fundamental for the development of selective therapeutic strategies, e.g., for the modulation of autoimmune responses or for the immunotherapy of cancer.
2014-07-10T13:08:09Z
2014-07-10T13:08:09Z
2012
Article
Layers of dendritic cell-mediated T cell tolerance, their regulation and the prevention of autoimmunity. 2012, 3:183 Front Immunol
1664-3224
22783257
10.3389/fimmu.2012.00183
http://hdl.handle.net/10033/322783
Frontiers in immunology
en
Archived with thanks to Frontiers in immunology
oai:repository.helmholtz-hzi.de:10033/3323492019-08-30T11:37:24Zcom_10033_56876col_10033_56896
Rapid rebound of the Treg compartment in DEREG mice limits the impact of Treg depletion on mycobacterial burden, but prevents autoimmunity.
Berod, Luciana
Stüve, Philipp
Varela, Filipa
Behrends, Jochen
Swallow, Maxine
Kruse, Friederike
Krull, Freyja
Ghorbani, Peyman
Mayer, Christian T
Hölscher, Christoph
Sparwasser, Tim
The development of an effective vaccine against tuberculosis (Tb) represents one of the major medical challenges of this century. Mycobacterium bovis Bacille Calmette-Guerin (BCG), the only vaccine available at present, is mostly effective at preventing disseminated Tb in children, but shows variable protection against pulmonary Tb, the most common form in adults. The reasons for this poor efficacy are not completely understood, but there is evidence that T regulatory cells (Tregs) might be involved. Similarly, Tregs have been associated with the immunosuppression observed in patients infected with Tb and are therefore believed to play a role in pathogen persistence. Thus, Treg depletion has been postulated as a novel strategy to potentiate M. bovis BCG vaccination on one side, while on the other, employed as a therapeutic approach during chronic Tb infection. Yet since Tregs are critically involved in controlling autoimmune inflammation, elimination of Tregs may therefore also incur the danger of an excessive inflammatory immune response. Thus, understanding the dynamics and function of Tregs during mycobacterial infection is crucial to evaluate the potential of Treg depletion as a medical option. To address this, we depleted Tregs after infection with M. bovis BCG or Mycobacterium tuberculosis (Mtb) using DEREG mice, which express the diphtheria toxin (DT) receptor under the control of the FoxP3 locus, thereby allowing the selective depletion of FoxP3+ Tregs. Our results show that after depletion, the Treg niche is rapidly refilled by a population of DT-insensitive Tregs (diTregs) and bacterial load remains unchanged. On the contrary, impaired rebound of Tregs in DEREG × FoxP3GFP mice improves pathogen burden, but is accompanied by detrimental autoimmune inflammation. Therefore, our study provides the proof-of-principle that, although a high degree of Treg depletion may contribute to the control of mycobacterial infection, it carries the risk of autoimmunity.
2014-10-09T08:05:51Z
2014-10-09T08:05:51Z
2014
Article
Rapid rebound of the Treg compartment in DEREG mice limits the impact of Treg depletion on mycobacterial burden, but prevents autoimmunity. 2014, 9 (7):e102804 PLoS ONE
1932-6203
25050936
10.1371/journal.pone.0102804
http://hdl.handle.net/10033/332349
PloS one
en
Archived with thanks to PloS one
oai:repository.helmholtz-hzi.de:10033/3323652019-08-30T11:37:24Zcom_10033_56876col_10033_56896
Depletion of regulatory T cells augments a vaccine-induced T effector cell response against the liver-stage of malaria but fails to increase memory.
Espinoza Mora, Maria del Rosario
Steeg, Christiane
Tartz, Susanne
Heussler, Volker
Sparwasser, Tim
Link, Andreas
Fleischer, Bernhard
Jacobs, Thomas
Regulatory T cells (T(reg)) have been shown to restrict vaccine-induced T cell responses in different experimental models. In these studies CD4(+)CD25(+) T(reg) were depleted using monoclonal antibodies against CD25, which might also interfere with CD25 on non-regulatory T cell populations and would have no effect on Foxp3(+)CD25(-) T(reg). To obtain more insights in the specific function of T(reg) during vaccination we used mice that are transgenic for a bacterial artificial chromosome expressing a diphtheria toxin (DT) receptor-eGFP fusion protein under the control of the foxp3 gene locus (depletion of regulatory T cell mice; DEREG). As an experimental vaccine-carrier recombinant Bordetella adenylate cyclase toxoid fused with a MHC-class I-restricted epitope of the circumsporozoite protein (ACT-CSP) of Plasmodium berghei (Pb) was used. ACT-CSP was shown by us previously to introduce the CD8+ epitope of Pb-CSP into the MHC class I presentation pathway of professional antigen-presenting cells (APC). Using this system we demonstrate here that the number of CSP-specific T cells increases when T(reg) are depleted during prime but also during boost immunization. Importantly, despite this increase of T effector cells no difference in the number of antigen-specific memory cells was observed.
2014-10-09T09:21:53Z
2014-10-09T09:21:53Z
2014
Article
Depletion of regulatory T cells augments a vaccine-induced T effector cell response against the liver-stage of malaria but fails to increase memory. 2014, 9 (8):e104627 PLoS ONE
1932-6203
25115805
10.1371/journal.pone.0104627
http://hdl.handle.net/10033/332365
PloS one
en
Archived with thanks to PloS one
oai:repository.helmholtz-hzi.de:10033/3344812019-08-30T11:28:51Zcom_10033_56876col_10033_56896
FoxP3+ Regulatory T Cells Determine Disease Severity in Rodent Models of Inflammatory Neuropathies.
Meyer Zu Hörste, Gerd
Cordes, Steffen
Mausberg, Anne K
Zozulya, Alla L
Wessig, Carsten
Sparwasser, Tim
Mathys, Christian
Wiendl, Heinz
Hartung, Hans-Peter
Kieseier, Bernd C
Department of Neurology, Heinrich-Heine-University, Medical Faculty, Düsseldorf, Germany.
Inflammatory neuropathies represent disabling human autoimmune disorders with considerable disease variability. Animal models provide insights into defined aspects of their disease pathogenesis. Forkhead box P3 (FoxP3)+ regulatory T lymphocytes (Treg) are anti-inflammatory cells that maintain immune tolerance and counteract tissue damage in a variety of immune-mediated disorders. Dysfunction or a reduced frequency of Tregs have been associated with different human autoimmune disorders. We here analyzed the functional relevance of Tregs in determining disease manifestation and severity in murine models of autoimmune neuropathies. We took advantage of the DEREG mouse system allowing depletion of Treg with high specificity as well as anti-CD25 directed antibodies to deplete Tregs in mice in actively induced experimental autoimmune neuritis (EAN). Furthermore antibody-depletion was performed in an adoptive transfer model of chronic neuritis. Early Treg depletion increased clinical EAN severity both in active and adoptive transfer chronic neuritis. This was accompanied by increased proliferation of myelin specific T cells and histological signs of peripheral nerve inflammation. Late stage Treg depletion after initial disease manifestation however did not exacerbate inflammatory neuropathy symptoms further. We conclude that Tregs determine disease severity in experimental autoimmune neuropathies during the initial priming phase, but have no major disease modifying function after disease manifestation. Potential future therapeutic approaches targeting Tregs should thus be performed early in inflammatory neuropathies.
2014-11-11T13:10:24Z
2014-11-11T13:10:24Z
2014
Article
FoxP3+ Regulatory T Cells Determine Disease Severity in Rodent Models of Inflammatory Neuropathies. 2014, 9 (10):e108756 PLoS ONE
1932-6203
25286182
10.1371/journal.pone.0108756
http://hdl.handle.net/10033/334481
PloS one
en
oai:repository.helmholtz-hzi.de:10033/3385582019-08-30T11:36:04Zcom_10033_56876col_10033_56896
Advantages of Foxp3(+) regulatory T cell depletion using DEREG mice.
Mayer, Christian T
Lahl, Katharina
Milanez-Almeida, Pedro
Watts, Deepika
Dittmer, Ulf
Fyhrquist, Nanna
Huehn, Jochen
Kopf, Manfred
Kretschmer, Karsten
Rouse, Barry
Sparwasser, Tim
Several mechanisms enable immunological self-tolerance. Regulatory T cells (Tregs) are a specialized T cell subset that prevents autoimmunity and excessive immune responses, but can also mediate detrimental tolerance to tumors and pathogens in a Foxp3-dependent manner. Genetic tools exploiting the foxp3 locus including bacterial artificial chromosome (BAC)-transgenic DEREG mice have provided essential information on Treg biology and the potential therapeutic modulation of tolerance. In DEREG mice, Foxp3(+) Tregs selectively express eGFP and diphtheria toxin (DT) receptor, allowing for the specific depletion of Tregs through DT administration. We here provide a detailed overview about important considerations such as DT toxicity, which affects any mouse strain treated with DT, and Treg rebound after depletion. Additionally, we point out the specific advantages of BAC-transgenic DEREG mice including their suitability to study organ-specific autoimmunity such as type I diabetes. Moreover, we discuss recent insights into the role of Tregs in viral infections. In summary, DEREG mice are an important tool to study Treg-mediated tolerance and its therapeutic circumvention.
2015-01-19T15:57:32Z
2015-01-19T15:57:32Z
2014-11
Article
Advantages of Foxp3(+) regulatory T cell depletion using DEREG mice. 2014, 2 (3):162-5 Immun Inflamm Dis
2050-4527
25505550
10.1002/iid3.33
http://hdl.handle.net/10033/338558
Immunity, inflammation and disease
en
oai:repository.helmholtz-hzi.de:10033/3388592019-08-30T11:36:05Zcom_10033_56876col_10033_56896
Regulatory T cells promote a protective Th17-associated immune response to intestinal bacterial infection with C. rodentium.
Wang, Z
Friedrich, C
Hagemann, S C
Korte, W H
Goharani, N
Cording, S
Eberl, G
Sparwasser, Tim
Lochner, M
Institute of Infection Immunology, TWINCORE, Centre for Experimental and Clinical Infection Research,Feodor-Lyner-Str. 7, 30625 Hannover, Germany.
Intestinal infection with the mouse pathogen Citrobacter rodentium induces a strong local Th17 response in the colon. Although this inflammatory immune response helps to clear the pathogen, it also induces inflammation-associated pathology in the gut and thus, has to be tightly controlled. In this project, we therefore studied the impact of Foxp3(+) regulatory T cells (Treg) on the infectious and inflammatory processes elicited by the bacterial pathogen C. rodentium. Surprisingly, we found that depletion of Treg by diphtheria toxin in the Foxp3(DTR) (DEREG) mouse model resulted in impaired bacterial clearance in the colon, exacerbated body weight loss, and increased systemic dissemination of bacteria. Consistent with the enhanced susceptibility to infection, we found that the colonic Th17-associated T-cell response was impaired in Treg-depleted mice, suggesting that the presence of Treg is crucial for the establishment of a functional Th17 response after the infection in the gut. As a consequence of the impaired Th17 response, we also observed less inflammation-associated pathology in the colons of Treg-depleted mice. Interestingly, anti-interleukin (IL)-2 treatment of infected Treg-depleted mice restored Th17 induction, indicating that Treg support the induction of a protective Th17 response during intestinal bacterial infection by consumption of local IL-2.
2015-01-26T11:47:37Z
2015-01-26T11:47:37Z
2014-11
Article
Regulatory T cells promote a protective Th17-associated immune response to intestinal bacterial infection with C. rodentium. 2014, 7 (6):1290-301 Mucosal Immunol
1935-3456
24646939
10.1038/mi.2014.17
http://hdl.handle.net/10033/338859
Mucosal immunology
en
oai:repository.helmholtz-hzi.de:10033/3463272019-08-30T11:37:23Zcom_10033_56876col_10033_56896
Regulatory T cells suppress muscle inflammation and injury in muscular dystrophy.
Villalta, S Armando
Rosenthal, Wendy
Martinez, Leonel
Kaur, Amanjot
Sparwasser, Tim
Tidball, James G
Margeta, Marta
Spencer, Melissa J
Bluestone, Jeffrey A
Institute for Infection Immunology, Twincore, Hannover 30625, Germany
We examined the hypothesis that regulatory T cells (Tregs) modulate muscle injury and inflammation in the mdx mouse model of Duchenne muscular dystrophy (DMD). Although Tregs were largely absent in the muscle of wild-type mice and normal human muscle, they were present in necrotic lesions, displayed an activated phenotype, and showed increased expression of interleukin-10 (IL-10) in dystrophic muscle from mdx mice. Depletion of Tregs exacerbated muscle injury and the severity of muscle inflammation, which was characterized by an enhanced interferon-γ (IFN-γ) response and activation of M1 macrophages. To test the therapeutic value of targeting Tregs in muscular dystrophy, we treated mdx mice with IL-2/anti-IL-2 complexes and found that Tregs and IL-10 concentrations were increased in muscle, resulting in reduced expression of cyclooxygenase-2 and decreased myofiber injury. These findings suggest that Tregs modulate the progression of muscular dystrophy by suppressing type 1 inflammation in muscle associated with muscle fiber injury, and highlight the potential of Treg-modulating agents as therapeutics for DMD.
2015-03-09T10:19:45Z
2015-03-09T10:19:45Z
2014-10-15
Article
Regulatory T cells suppress muscle inflammation and injury in muscular dystrophy. 2014, 6 (258):258ra142 Sci Transl Med
1946-6242
25320234
10.1126/scitranslmed.3009925
http://hdl.handle.net/10033/346327
Science translational medicine
en
oai:repository.helmholtz-hzi.de:10033/5281302019-08-30T11:27:46Zcom_10033_56876col_10033_56896
Towards the generation of B-cell receptor retrogenic mice.
Freitag, Jenny
Heink, Sylvia
Roth, Edith
Wittmann, Jürgen
Jäck, Hans-Martin
Kamradt, Thomas
Institute for Infection Immunology, Centre for Experimental and Clinical Infection Research, a joint venture between the Medical, School Hannover (MHH) and the Helmholtz Centre for Infection Research (HZI), Hannover, Germany.
Transgenic expression of B- and T-cell receptors (BCRs and TCRs, respectively) has been a standard tool to study lymphocyte development and function in vivo. The generation of transgenic mice is time-consuming and, therefore, a faster method to study the biology of defined lymphocyte receptors in vivo would be highly welcome. Using 2A peptide-linked multicistronic retroviral vectors to transduce stem cells, TCRs can be expressed rapidly in mice of any background. We aimed at adopting this retrogenic technology to the in vivo expression of BCRs. Using a well characterised BCR specific for hen egg lysozyme (HEL), we achieved surface expression of the retrogenically encoded BCR in a Rag-deficient pro B-cell line in vitro. In vivo, retrogenic BCRs were detectable only intracellularly but not on the surface of B cells from wild type or Rag2-deficient mice. This data, together with the fact that no BCR retrogenic mouse model has been published in the 7 years since the method was originally published for TCRs, strongly suggests that achieving BCR-expression in vivo with retrogenic technology is highly challenging if not impossible.
2015-04-10T12:52:31Z
2015-04-10T12:52:31Z
2014
Article
Towards the generation of B-cell receptor retrogenic mice. 2014, 9 (10):e109199 PLoS ONE
1932-6203
25296340
10.1371/journal.pone.0109199
http://hdl.handle.net/10033/528130
PloS one
en
oai:repository.helmholtz-hzi.de:10033/5504872019-08-30T11:25:43Zcom_10033_56876col_10033_56896
CD4+ natural regulatory T cells prevent experimental cerebral malaria via CTLA-4 when expanded in vivo.
Haque, Ashraful
Best, Shannon E
Amante, Fiona H
Mustafah, Seri
Desbarrieres, Laure
de Labastida, Fabian
Sparwasser, Tim
Hill, Geoffrey R
Engwerda, Christian R
Animals
Antigens, CD
CD4-Positive T-Lymphocytes
CD8-Positive T-Lymphocytes
CTLA-4 Antigen
Cell Proliferation
Forkhead Transcription Factors
Interleukin-10
Malaria, Cerebral
Mice
Mice, Inbred C57BL
Plasmodium berghei
T-Lymphocytes, Regulatory
Studies in malaria patients indicate that higher frequencies of peripheral blood CD4(+) Foxp3(+) CD25(+) regulatory T (Treg) cells correlate with increased blood parasitemia. This observation implies that Treg cells impair pathogen clearance and thus may be detrimental to the host during infection. In C57BL/6 mice infected with Plasmodium berghei ANKA, depletion of Foxp3(+) cells did not improve parasite control or disease outcome. In contrast, elevating frequencies of natural Treg cells in vivo using IL-2/anti-IL-2 complexes resulted in complete protection against severe disease. This protection was entirely dependent upon Foxp3(+) cells and resulted in lower parasite biomass, impaired antigen-specific CD4(+) T and CD8(+) T cell responses that would normally promote parasite tissue sequestration in this model, and reduced recruitment of conventional T cells to the brain. Furthermore, Foxp3(+) cell-mediated protection was dependent upon CTLA-4 but not IL-10. These data show that T cell-mediated parasite tissue sequestration can be reduced by regulatory T cells in a mouse model of malaria, thereby limiting malaria-induced immune pathology.
2015-04-23T08:56:44Z
2015-04-23T08:56:44Z
2010
Article
CD4+ natural regulatory T cells prevent experimental cerebral malaria via CTLA-4 when expanded in vivo. 2010, 6 (12):e1001221 PLoS Pathog.
1553-7374
21170302
10.1371/journal.ppat.1001221
http://hdl.handle.net/10033/550487
PLoS pathogens
en
oai:repository.helmholtz-hzi.de:10033/5572282019-08-30T11:26:42Zcom_10033_56876col_10033_56896
Immunostimulatory Effects Triggered by Enterococcus faecalis CECT7121 Probiotic Strain Involve Activation of Dendritic Cells and Interferon-Gamma Production.
Molina, Matías Alejandro
Díaz, Ailén Magalí
Hesse, Christina
Ginter, Wiebke
Gentilini, María Virginia
Nuñez, Guillermo Gabriel
Canellada, Andrea Mercedes
Sparwasser, Tim
Berod, Luciana
Castro, Marisa Silvia
Manghi, Marcela Alejandra
Helmholtz Centre for infection research, Inhoffenstr. 7, 38124 Braunschweig, Germany.
Probiotics can modulate the immune system, conferring beneficial effects on the host. Understanding how these microorganisms contribute to improve the health status is still a challenge. Previously, we have demonstrated that Enterococcus faecalis CECT7121 implants itself and persists in the murine gastrointestinal tract, and enhances and skews the profile of cytokines towards the Th1 phenotype in several biological models. Given the importance of dendritic cells (DCs) in the orchestration of immunity, the aim of this work was to elucidate the influence of E. faecalis CECT7121 on DCs and the outcome of the immune responses. In this work we show that E. faecalis CECT7121 induces a strong dose-dependent activation of DCs and secretion of high levels of IL-12, IL-6, TNFα, and IL-10. This stimulation is dependent on TLR signaling, and skews the activation of T cells towards the production of IFNγ. The influence of this activation in the establishment of Th responses in vivo shows the accumulation of specific IFNγ-producing cells. Our findings indicate that the activation exerted by E. faecalis CECT7121 on DCs and its consequence on the cellular adaptive immune response may have broad therapeutic implications in immunomodulation.
2015-06-18T08:43:08Z
2015-06-18T08:43:08Z
2015
Article
Immunostimulatory Effects Triggered by Enterococcus faecalis CECT7121 Probiotic Strain Involve Activation of Dendritic Cells and Interferon-Gamma Production. 2015, 10 (5):e0127262 PLoS ONE
1932-6203
25978357
10.1371/journal.pone.0127262
http://hdl.handle.net/10033/557228
PloS one
en
oai:repository.helmholtz-hzi.de:10033/5785952019-08-30T11:30:58Zcom_10033_56876col_10033_56896
Active suppression of intestinal CD4(+)TCRαβ(+) T-lymphocyte maturation during the postnatal period.
Torow, Natalia
Yu, Kai
Hassani, Kasra
Freitag, Jenny
Schulz, Olga
Basic, Marijana
Brennecke, Anne
Sparwasser, Tim
Wagner, Norbert
Bleich, André
Lochner, Matthias
Weiss, Siegfried
Förster, Reinhold
Pabst, Oliver
Hornef, Mathias W
TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Medical School, Hannover (MHH) and the Helmholtz Centre for Infection Research (HZI), Feodor-Lynen-Stra e 7, 30625 Hannover, Germany
Priming of the mucosal immune system during the postnatal period substantially influences host-microbial interaction and susceptibility to immune-mediated diseases in adult life. The underlying mechanisms are ill defined. Here we show that shortly after birth, CD4 T cells populate preformed lymphoid structures in the small intestine and quickly acquire a distinct transcriptional profile. T-cell recruitment is independent of microbial colonization and innate or adaptive immune stimulation but requires β7 integrin expression. Surprisingly, neonatal CD4 T cells remain immature throughout the postnatal period under homeostatic conditions but undergo maturation and gain effector function on barrier disruption. Maternal SIgA and regulatory T cells act in concert to prevent immune stimulation and maintain the immature phenotype of CD4 T cells in the postnatal intestine during homeostasis. Active suppression of CD4 T-cell maturation during the postnatal period might contribute to prevent auto-reactivity, sustain a broad TCR repertoire and establish life-long immune homeostasis.
2015-09-22T13:17:24Z
2015-09-22T13:17:24Z
2015
Article
Active suppression of intestinal CD4(+)TCRαβ(+) T-lymphocyte maturation during the postnatal period. 2015, 6:7725 Nat Commun
2041-1723
26195040
10.1038/ncomms8725
http://hdl.handle.net/10033/578595
Nature communications
en
oai:repository.helmholtz-hzi.de:10033/5797952019-08-30T11:30:58Zcom_10033_56876col_10033_56896
Antigen targeting to dendritic cells combined with transient regulatory T cell inhibition results in long-term tumor regression.
Unger, Wendy Wj
Mayer, Christian T
Engels, Steef
Hesse, Christina
Perdicchio, Maurizio
Puttur, Franz
Streng-Ouwehand, Ingeborg
Litjens, Manja
Kalay, Hakan
Berod, Luciana
Sparwasser, Tim
van Kooyk, Yvette
Institute of Experimental Virology, Twincore, Centre for Experimental and Clinical Infection Research, Hannover, Germany.
Therapeutic vaccinations against cancer are still largely ineffective. Major caveats are inefficient delivery of tumor antigens to dendritic cells (DCs) and excessive immune suppression by Foxp3(+) regulatory T cells (Tregs), resulting in defective T cell priming and failure to induce tumor regression. To circumvent these problems we evaluated a novel combinatorial therapeutic strategy. We show that tumor antigen targeting to DC-SIGN in humanized hSIGN mice via glycans or specific antibodies induces superior T cell priming. Next, this targeted therapy was combined with transient Foxp3(+) Treg depletion employing hSIGNxDEREG mice. While Treg depletion alone slightly delayed B16-OVA melanoma growth, only the combination therapy instigated long-term tumor regression in a substantial fraction of mice. This novel strategy resulted in optimal generation of antigen-specific activated CD8(+) T cells which accumulated in regressing tumors. Notably, Treg depletion also allowed the local appearance of effector T cells specific for endogenous B16 antigens. This indicates that antitumor immune responses can be broadened by therapies aimed at controlling Tregs in tumor environments. Thus, transient inhibition of Treg-mediated immune suppression potentiates DC targeted antigen vaccination and tumor-specific immunity.
2015-10-16T13:04:19Z
2015-10-16T13:04:19Z
2015-08
Article
Antigen targeting to dendritic cells combined with transient regulatory T cell inhibition results in long-term tumor regression. 2015, 4 (8):e970462 Oncoimmunology
2162-4011
26405564
10.4161/21624011.2014.970462
http://hdl.handle.net/10033/579795
Oncoimmunology
ENG
oai:repository.helmholtz-hzi.de:10033/5833242019-08-30T11:25:04Zcom_10033_56876col_10033_56896
Antigen receptor-mediated depletion of FOXP3 in induced regulatory T-lymphocytes via PTPN2 and FOXO1
Bothur, Evita
Raifer, Hartmann
Haftmann, Claudia
Stittrich, Anna-Barbara
Brüstle, Anne
Brenner, Dirk
Bollig, Nadine
Bieringer, Maria
Kang, Chol-Ho
Reinhard, Katharina
Camara, Bärbel
Huber, Magdalena
Visekruna, Alexander
Steinhoff, Ulrich
Repenning, Antje
Bauer, Uta-Maria
Sexl, Veronika
Radbruch, Andreas
Sparwasser, Tim
Mashreghi, Mir-Farzin
Wah Mak, Tak
Lohoff, Michael
TWINCORE, Centre for Experimental and Clinical Infection Research GmbH, Feodor-Lynen-Str. 3-7, 30625 Hannover, Germany.
2015-12-07T15:37:25Z
2015-12-07T15:37:25Z
2015-10-13
Article
Antigen receptor-mediated depletion of FOXP3 in induced regulatory T-lymphocytes via PTPN2 and FOXO1 2015, 6:8576 Nature Communications
2041-1723
10.1038/ncomms9576
http://hdl.handle.net/10033/583324
Nature Communications
http://www.nature.com/doifinder/10.1038/ncomms9576
oai:repository.helmholtz-hzi.de:10033/5937232019-08-30T11:36:32Zcom_10033_56876col_10033_56896
FoxP3+ regulatory T cells essentially contribute to peripheral CD8+ T-cell tolerance induced by steady-state dendritic cells.
Schildknecht, Anita
Brauer, Sabine
Brenner, Corinne
Lahl, Katharina
Schild, Hansjörg
Sparwasser, Tim
Probst, Hans Christian
van den Broek, Maries
TWINCORE, Centre for Experimental and Clinical Infection Research GmbH, Feodor-Lynen-Str. 3-7, 30625 Hannover, Germany.
Animals
Antigens, CD
CD8-Positive T-Lymphocytes
CTLA-4 Antigen
Dendritic Cells
Forkhead Transcription Factors
Immune Tolerance
Interleukin-10
Mice
Mice, Inbred C57BL
Mice, Transgenic
Phenotype
T-Lymphocytes, Regulatory
Peripheral T-cell tolerance is thought to significantly contribute to the prevention of autoimmunity, and it has been shown that antigen-presenting steady-state dendritic cells efficiently induce peripheral tolerance. We previously showed that dendritic-cell-induced tolerance is a T-cell-intrinsic process that depends on coinhibitory molecules such as programmed death-1. Here we specifically analyze the involvement of FoxP3(+) regulatory T cells, which are known to be important for maintenance of self-tolerance. We show that antigen presentation by steady-state dendritic cells failed to induce peripheral tolerance in the absence of FoxP3(+) regulatory T cells but induced protective CD8(+) T-cell-mediated immunity instead. Regulatory T-cell-depleted mice had massively increased numbers of dendritic cells in lymph nodes. Dendritic cells isolated from mice without regulatory T cells had up-regulated costimulatory molecules and showed stronger T-cell stimulatory capacity ex vivo, suggesting that regulatory T cells contribute to peripheral tolerance by keeping the dendritic cells in an immature state. Using blocking antibodies, we demonstrate that CTLA-4 but not IL-10 is necessary for control of dendritic cells by regulatory T cells.
2016-01-18T14:22:56Z
2016-01-18T14:22:56Z
2010-01-05
Article
FoxP3+ regulatory T cells essentially contribute to peripheral CD8+ T-cell tolerance induced by steady-state dendritic cells. 2010, 107 (1):199-203 Proc. Natl. Acad. Sci. U.S.A.
1091-6490
20018763
10.1073/pnas.0910620107
http://hdl.handle.net/10033/593723
Proceedings of the National Academy of Sciences of the United States of America
en
oai:repository.helmholtz-hzi.de:10033/5937432019-08-30T11:32:59Zcom_10033_56876col_10033_56896
Secretory phospholipase A2-IID is an effector molecule of CD4 + CD25 + regulatory T cells
von Allmen, Caroline E.
Schmitz, Nicole
Bauer, Monika
Hinton, Heather J.
Kurrer, Michael O.
Buser, Regula B.
Gwerder, Myriam
Muntwiler, Simone
Sparwasser, Tim
Beerli, Roger R.
Bachmann, Martin F.
TWINCORE, Centre for Experimental and Clinical Infection Research GmbH, Feodor-Lynen-Str. 3-7, 30625 Hannover, Germany.
2016-01-18T14:07:05Z
2016-01-18T14:07:05Z
2009-07-14
Article
Secretory phospholipase A2-IID is an effector molecule of CD4 + CD25 + regulatory T cells 2009, 106 (28):11673 Proceedings of the National Academy of Sciences
1091-6490
19564598
10.1073/pnas.0812569106
http://hdl.handle.net/10033/593743
Proceedings of the National Academy of Sciences
http://www.pnas.org/lookup/doi/10.1073/pnas.0812569106
oai:repository.helmholtz-hzi.de:10033/5937492019-08-30T11:36:32Zcom_10033_56876col_10033_56896
Transient depletion of regulatory T cells in transgenic mice reactivates virus-specific CD8+ T cells and reduces chronic retroviral set points.
Dietze, Kirsten K
Zelinskyy, Gennadiy
Gibbert, Kathrin
Schimmer, Simone
Francois, Sandra
Myers, Lara
Sparwasser, Tim
Hasenkrug, Kim J
Dittmer, Ulf
TWINCORE, Centre for Experimental and Clinical Infection Research GmbH, Feodor-Lynen-Str. 3-7, 30625 Hannover, Germany.
Animals
CD8-Positive T-Lymphocytes
Chronic Disease
Cytokines
Lymphocyte Depletion
Mice
Mice, Transgenic
Retroviridae Infections
T-Lymphocytes, Regulatory
Although chronic infections with viruses such as HIV and hepatitis C virus have been associated with regulatory T cell (Treg)-mediated suppression of virus-specific CD8(+) T-cell activity, no causal relationship between Tregs and chronic viral set points has been established. Using transgenic mice in which Tregs can be selectively ablated, we now show that transient depletion of Tregs during a chronic retroviral infection allows exhausted CD8(+) T cells to regain antiviral functions, including secretion of cytokines, production of cytotoxic molecules, and virus-specific cytolytic activity. Furthermore, short-term Treg ablation resulted in long-term reductions in chronic virus loads. These results demonstrate that Treg-mediated immunosuppression can be a significant factor in the maintenance of chronic viral infections and that Treg-targeted immunotherapy could be a valuable component in therapeutic strategies to treat chronic infectious diseases.
2016-01-18T14:55:33Z
2016-01-18T14:55:33Z
2011-02-08
Article
Transient depletion of regulatory T cells in transgenic mice reactivates virus-specific CD8+ T cells and reduces chronic retroviral set points. 2011, 108 (6):2420-5 Proc. Natl. Acad. Sci. U.S.A.
1091-6490
21262821
10.1073/pnas.1015148108
http://hdl.handle.net/10033/593749
Proceedings of the National Academy of Sciences of the United States of America
en
oai:repository.helmholtz-hzi.de:10033/5937532019-08-30T11:36:32Zcom_10033_56876col_10033_56896
Mouse cytomegalovirus infection overrules T regulatory cell suppression on natural killer cells.
Lindenberg, Marc
Solmaz, Gulhas
Puttur, Franz
Sparwasser, Tim
TWINCORE, Centre for Experimental and Clinical Infection Research GmbH, Feodor-Lynen-Str. 3-7, 30625 Hannover, Germany.
Adaptive Immunity
Animals
Forkhead Transcription Factors
Herpesviridae Infections
Homeostasis
Interferon-gamma
Killer Cells, Natural
Lymphocyte Activation
Lymphocyte Count
Lymphocyte Depletion
Male
Mice
Muromegalovirus
Phenotype
T-Lymphocyte Subsets
T-Lymphocytes, Regulatory
Viral Load
Cytomegalovirus establishes lifelong persistency in the host and leads to life threatening situations in immunocompromised patients. FoxP3+ T regulatory cells (Tregs) critically control and suppress innate and adaptive immune responses. However, their specific role during MCMV infection, especially pertaining to their interaction with NK cells, remains incompletely defined.
2016-01-18T15:42:57Z
2016-01-18T15:42:57Z
2014
Article
Mouse cytomegalovirus infection overrules T regulatory cell suppression on natural killer cells. 2014, 11:145 Virol. J.
1743-422X
25108672
10.1186/1743-422X-11-145
http://hdl.handle.net/10033/593753
Virology journal
en
oai:repository.helmholtz-hzi.de:10033/5955262019-08-30T11:36:32Zcom_10033_56876col_10033_56896
Foxp3+ regulatory T cells control persistence of viral CNS infection.
Reuter, Dajana
Sparwasser, Tim
Hünig, Thomas
Schneider-Schaulies, Jürgen
TWINCORE, Centre for Experimental and Clinical Infection Research GmbH, Feodor-Lynen-Str. 3-7, 30625 Hannover, Germany.
Animals
Brain
Central Nervous System Viral Diseases
Cercopithecus aethiops
Flow Cytometry
Forkhead Transcription Factors
Immunosuppression
Measles
Measles virus
Mice
Mice, Inbred C57BL
T-Lymphocytes, Regulatory
Vero Cells
We earlier established a model of a persistent viral CNS infection using two week old immunologically normal (genetically unmodified) mice and recombinant measles virus (MV). Using this model infection we investigated the role of regulatory T cells (Tregs) as regulators of the immune response in the brain, and assessed whether the persistent CNS infection can be modulated by manipulation of Tregs in the periphery. CD4(+) CD25(+) Foxp3(+) Tregs were expanded or depleted during the persistent phase of the CNS infection, and the consequences for the virus-specific immune response and the extent of persistent infection were analyzed. Virus-specific CD8(+) T cells predominantly recognising the H-2D(b)-presented viral hemagglutinin epitope MV-H(22-30) (RIVINREHL) were quantified in the brain by pentamer staining. Expansion of Tregs after intraperitoneal (i.p.) application of the superagonistic anti-CD28 antibody D665 inducing transient immunosuppression caused increased virus replication and spread in the CNS. In contrast, depletion of Tregs using diphtheria toxin (DT) in DEREG (depletion of regulatory T cells)-mice induced an increase of virus-specific CD8(+) effector T cells in the brain and caused a reduction of the persistent infection. These data indicate that manipulation of Tregs in the periphery can be utilized to regulate virus persistence in the CNS.
2016-02-03T14:47:42Z
2016-02-03T14:47:42Z
2012
Article
Foxp3+ regulatory T cells control persistence of viral CNS infection. 2012, 7 (3):e33989 PLoS ONE
1932-6203
22448284
10.1371/journal.pone.0033989
http://hdl.handle.net/10033/595526
PloS one
en
oai:repository.helmholtz-hzi.de:10033/5955292019-08-30T11:33:02Zcom_10033_56876col_10033_56896
Regulatory T cells suppress antiviral immune responses and increase viral loads during acute infection with a lymphotropic retrovirus.
Zelinskyy, Gennadiy
Dietze, Kirsten
Sparwasser, Tim
Dittmer, Ulf
TWINCORE, Centre for Experimental and Clinical Infection Research GmbH, Feodor-Lynen-Str. 3-7, 30625 Hannover, Germany.
Acute Disease
Animals
CD8-Positive T-Lymphocytes
Disease Models, Animal
Friend murine leukemia virus
Leukemia, Experimental
Mice
Retroviridae Infections
Spleen
T-Lymphocytes, Regulatory
Tumor Virus Infections
Viral Load
2016-02-03T15:09:20Z
2016-02-03T15:09:20Z
2009-08
Article
Regulatory T cells suppress antiviral immune responses and increase viral loads during acute infection with a lymphotropic retrovirus. 2009, 5 (8):e1000406 PLoS Pathog.
1553-7374
19714239
10.1371/journal.ppat.1000406
http://hdl.handle.net/10033/595529
PLoS pathogens
en
oai:repository.helmholtz-hzi.de:10033/5956052019-08-30T11:36:59Zcom_10033_56876col_10033_56896
Salmonella enterica serovar Typhimurium infection-induced CD11b+ Gr1+ cells ameliorate allergic airway inflammation.
Ganesh, Venkateswaran
Baru, Abdul Mannan
Hesse, Christina
Friedrich, Christin
Glage, Silke
Gohmert, Melanie
Jänke, Christine
Sparwasser, Tim
Animals
Antigens, CD11b
Cell Differentiation
Forkhead Transcription Factors
GATA3 Transcription Factor
Hypersensitivity
Inflammation
Interleukin-4
Longitudinal Studies
Lung
Mice
Mice, Inbred BALB C
Myeloid Cells
Receptors, Chemokine
Salmonella Infections
Salmonella typhimurium
T-Lymphocytes, Regulatory
Th2 Cells
Allergies are mainly characterized as an unrestrained Th2-biased immune response. Epidemiological data associate protection from allergic diseases with the exposure to certain infectious agents during early stages of life. Modulation of the immune response by pathogens has been considered to be a major factor influencing this protection. Recent evidence indicates that immunoregulatory mechanisms induced upon infection ameliorate allergic disorders. A longitudinal study has demonstrated reduced frequency and incidence of asthma in children who reported a prior infection with Salmonella. Experimental studies involving Salmonella enterica serovar Typhimurium-infected murine models have confirmed protection from induced allergic airway inflammation; however, the underlying cause leading to this amelioration remains incompletely defined. In this study, we aimed to delineate the regulatory function of Salmonella Typhimurium infection in the amelioration of allergic airway inflammation in mice. We observed a significant increase in CD11b+ Gr1+ myeloid cell populations in mice after infection with S. Typhimurium. Using in vitro and in vivo studies, we confirmed that these myeloid cells reduce airway inflammation by influencing Th2 cells. Further characterization showed that the CD11b+ Gr1+ myeloid cells exhibited their inhibitory effect by altering GATA-3 expression and interleukin-4 (IL-4) production by Th2 cells. These results indicate that the expansion of myeloid cells upon S. Typhimurium infection could potentially play a significant role in curtailing allergic airway inflammation. These findings signify the contribution of myeloid cells in preventing Th2-mediated diseases and suggest their possible application as therapeutics.
2016-02-04T15:02:20Z
2016-02-04T15:02:20Z
2014-03
Article
Salmonella enterica serovar Typhimurium infection-induced CD11b+ Gr1+ cells ameliorate allergic airway inflammation. 2014, 82 (3):1052-63 Infect. Immun.
1098-5522
24343652
10.1128/IAI.01378-13
http://hdl.handle.net/10033/595605
Infection and immunity
en
oai:repository.helmholtz-hzi.de:10033/6074092019-08-30T11:24:31Zcom_10033_56876col_10033_56896
Low-level regulatory T-cell activity is essential for functional type-2 effector immunity to expel gastrointestinal helminths.
Smith, K A
Filbey, K J
Reynolds, L A
Hewitson, J P
Harcus, Y
Boon, L
Sparwasser, Tim
Hämmerling, G
Maizels, R M
Twincore Centre for Experimental and Clinical Infection Research, a joint venture between the Medical School Hanover and the Helmholtz Centre for Infection Research, Hanover, Germany.
Helminth infection is frequently associated with the expansion of regulatory T cells (Tregs) and suppression of immune responses to bystander antigens. We show that infection of mice with the chronic gastrointestinal helminth Heligmosomoides polygyrus drives rapid polyclonal expansion of Foxp3(+)Helios(+)CD4(+) thymic (t)Tregs in the lamina propria and mesenteric lymph nodes while Foxp3(+)Helios(-)CD4(+) peripheral (p)Treg expand more slowly. Notably, in partially resistant BALB/c mice parasite survival positively correlates with Foxp3(+)Helios(+)CD4(+) tTreg numbers. Boosting of Foxp3(+)Helios(+)CD4(+) tTreg populations by administration of recombinant interleukin-2 (rIL-2):anti-IL-2 (IL-2C) complex increased worm persistence by diminishing type-2 responsiveness in vivo, including suppression of alternatively activated macrophage and granulomatous responses at the sites of infection. IL-2C also increased innate lymphoid cell (ILC) numbers, indicating that Treg functions dominate over ILC effects in this setting. Surprisingly, complete removal of Tregs in transgenic Foxp3-DTR mice also resulted in increased worm burdens, with "immunological chaos" evident in high levels of the pro-inflammatory cytokines IL-6 and interferon-γ. In contrast, worm clearance could be induced by anti-CD25 antibody-mediated partial depletion of early Treg, alongside increased T helper type 2 responses and without incurring pathology. These findings highlight the overarching importance of the early Treg response to infection and the non-linear association between inflammation and the prevailing Treg frequency.
2016-04-29T08:54:36Z
2016-04-29T08:54:36Z
2016-03
Article
Low-level regulatory T-cell activity is essential for functional type-2 effector immunity to expel gastrointestinal helminths. 2016, 9 (2):428-43 Mucosal Immunol
1935-3456
26286232
10.1038/mi.2015.73
http://hdl.handle.net/10033/607409
Mucosal immunology
en
oai:repository.helmholtz-hzi.de:10033/6095812019-08-30T11:29:47Zcom_10033_56876col_10033_56896
Sialic acid-modified antigens impose tolerance via inhibition of T-cell proliferation and de novo induction of regulatory T cells.
Perdicchio, Maurizio
Ilarregui, Juan M
Verstege, Marleen I
Cornelissen, Lenneke A M
Schetters, Sjoerd T T
Engels, Steef
Ambrosini, Martino
Kalay, Hakan
Veninga, Henrike
den Haan, Joke M M
van Berkel, Lisette A
Samsom, Janneke N
Crocker, Paul R
Sparwasser, Tim
Berod, Luciana
Garcia-Vallejo, Juan J
van Kooyk, Yvette
Unger, Wendy W J
Twincore, Institute for Experimental Virology, Hannover, Germany.
Sialic acids are negatively charged nine-carbon carboxylated monosaccharides that often cap glycans on glycosylated proteins and lipids. Because of their strategic location at the cell surface, sialic acids contribute to interactions that are critical for immune homeostasis via interactions with sialic acid-binding Ig-type lectins (siglecs). In particular, these interactions may be of importance in cases where sialic acids may be overexpressed, such as on certain pathogens and tumors. We now demonstrate that modification of antigens with sialic acids (Sia-antigens) regulates the generation of antigen-specific regulatory T (Treg) cells via dendritic cells (DCs). Additionally, DCs that take up Sia-antigen prevent formation of effector CD4(+)and CD8(+)T cells. Importantly, the regulatory properties endowed on DCs upon Sia-antigen uptake are antigen-specific: only T cells responsive to the sialylated antigen become tolerized. In vivo, injection of Sia-antigen-loaded DCs increased de novo Treg-cell numbers and dampened effector T-cell expansion and IFN-γ production. The dual tolerogenic features that Sia-antigen imposed on DCs are Siglec-E-mediated and maintained under inflammatory conditions. Moreover, loading DCs with Sia-antigens not only inhibited the function of in vitro-established Th1 and Th17 effector T cells but also significantly dampened ex vivo myelin-reactive T cells, present in the circulation of mice with experimental autoimmune encephalomyelitis. These data indicate that sialic acid-modified antigens instruct DCs in an antigen-specific tolerogenic programming, enhancing Treg cells and reducing the generation and propagation of inflammatory T cells. Our data suggest that sialylation of antigens provides an attractive way to induce antigen-specific immune tolerance.
2016-05-17T14:22:13Z
2016-05-17T14:22:13Z
2016-03-22
Article
Sialic acid-modified antigens impose tolerance via inhibition of T-cell proliferation and de novo induction of regulatory T cells. 2016, 113 (12):3329-34 Proc. Natl. Acad. Sci. U.S.A.
1091-6490
26941238
10.1073/pnas.1507706113
http://hdl.handle.net/10033/609581
Proceedings of the National Academy of Sciences of the United States of America
en
oai:repository.helmholtz-hzi.de:10033/6095662019-08-30T11:29:47Zcom_10033_56876col_10033_56896
Combination of nanoparticle-based therapeutic vaccination and transient ablation of regulatory T cells enhances anti-viral immunity during chronic retroviral infection.
Knuschke, Torben
Rotan, Olga
Bayer, Wibke
Sokolova, Viktoriya
Hansen, Wiebke
Sparwasser, Tim
Dittmer, Ulf
Epple, Matthias
Buer, Jan
Westendorf, Astrid M
TWINCORE, Centre for Experimental and Clinical Medicine, 30625 Hannover, Germany.
Regulatory T cells (Tregs) have been shown to limit anti-viral immunity during chronic retroviral infection and to restrict vaccine-induced T cell responses. The objective of the study was to assess whether a combinational therapy of nanoparticle-based therapeutic vaccination and concomitant transient ablation of Tregs augments anti-viral immunity and improves virus control in chronically retrovirus-infected mice. Therefore, chronically Friend retrovirus (FV)-infected mice were immunized with calcium phosphate (CaP) nanoparticles functionalized with TLR9 ligand CpG and CD8(+) or CD4(+) T cell epitope peptides (GagL85-93 or Env gp70123-141) of FV. In addition, Tregs were ablated during the immunization process. Reactivation of CD4(+) and CD8(+) effector T cells was analysed and the viral loads were determined.
2016-05-17T14:42:26Z
2016-05-17T14:42:26Z
2016
Article
Combination of nanoparticle-based therapeutic vaccination and transient ablation of regulatory T cells enhances anti-viral immunity during chronic retroviral infection. 2016, 13:24 Retrovirology
1742-4690
27076190
10.1186/s12977-016-0258-9
http://hdl.handle.net/10033/609566
Retrovirology
en
oai:repository.helmholtz-hzi.de:10033/6178272019-08-30T11:33:05Zcom_10033_56876col_10033_56896
The Special Relationship in the Development and Function of T Helper 17 and Regulatory T Cells.
Lochner, Matthias
Wang, Zuobai
Sparwasser, Tim
TWINCORE, Centre for Experimental and Clinical Medicine, 30625 Hannover, Germany.
T helper 17 (Th17) cells play an essential role in the clearance of extracellular pathogenic bacteria and fungi. However, this subset is critically involved in the pathology of many autoimmune diseases, e.g., psoriasis, multiple sclerosis, allergy, rheumatoid arthritis, and inflammatory bowel diseases in humans. Therefore, Th17 responses need to be tightly regulated in vivo to mediate effective host defenses against pathogens without causing excessive host tissue damage. Foxp3(+) regulatory T (Treg) cells play an important role in maintaining peripheral tolerance to self-antigens and in counteracting the inflammatory activity of effector T helper cell subsets. Although Th17 and Treg cells represent two CD4(+) T cell subsets with opposing principal functions, these cell types are functionally connected. In this review, we will first give an overview on the biology of Th17 cells and describe their development and in vivo function, followed by an account on the special developmental relationship between Th17 and Treg cells. We will describe the identification of Treg/Th17 intermediates and consider their lineage stability and function in vivo. Finally, we will discuss how Treg cells may regulate the Th17 cell response in the context of infection and inflammation, and elude on findings demonstrating that Treg cells can also have a prominent function in promoting the differentiation of Th17 cells.
2016-08-02T11:59:05Z
2016-08-02T11:59:05Z
2015
Article
The Special Relationship in the Development and Function of T Helper 17 and Regulatory T Cells. 2015, 136:99-129 Prog Mol Biol Transl Sci
1878-0814
26615094
10.1016/bs.pmbts.2015.07.013
http://hdl.handle.net/10033/617827
Progress in molecular biology and translational science
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
oai:repository.helmholtz-hzi.de:10033/6205882019-08-30T11:26:42Zcom_10033_56876col_10033_56896
Conventional Dendritic Cells Confer Protection against Mouse Cytomegalovirus Infection via TLR9 and MyD88 Signaling.
Puttur, Franz
Francozo, Marcela
Solmaz, Gülhas
Bueno, Carlos
Lindenberg, Marc
Gohmert, Melanie
Swallow, Maxine
Tufa, Dejene
Jacobs, Roland
Lienenklaus, Stefan
Kühl, Anja A
Borkner, Lisa
Cicin-Sain, Luka
Holzmann, Bernard
Wagner, Hermann
Berod, Luciana
Sparwasser, Tim
Twincore Centre of Experimental and Clinical Infection Research; a joint venture between the Hannover Medical School and the Helmholtz Centre for Infection Research, Hannover 30625, Germany.
Cytomegalovirus (CMV) is an opportunistic virus severely infecting immunocompromised individuals. In mice, endosomal Toll-like receptor 9 (TLR9) and downstream myeloid differentiation factor 88 (MyD88) are central to activating innate immune responses against mouse CMV (MCMV). In this respect, the cell-specific contribution of these pathways in initiating anti-MCMV immunity remains unclear. Using transgenic mice, we demonstrate that TLR9/MyD88 signaling selectively in CD11c(+) dendritic cells (DCs) strongly enhances MCMV clearance by boosting natural killer (NK) cell CD69 expression and IFN-γ production. In addition, we show that in the absence of plasmacytoid DCs (pDCs), conventional DCs (cDCs) promote robust NK cell effector function and MCMV clearance in a TLR9/MyD88-dependent manner. Simultaneously, cDC-derived IL-15 regulates NK cell degranulation by TLR9/MyD88-independent mechanisms. Overall, we compartmentalize the cellular contribution of TLR9 and MyD88 signaling in individual DC subsets and evaluate the mechanism by which cDCs control MCMV immunity.
2016-11-18T12:05:57Z
2016-11-18T12:05:57Z
2016-10-18
Article
Conventional Dendritic Cells Confer Protection against Mouse Cytomegalovirus Infection via TLR9 and MyD88 Signaling. 2016, 17 (4):1113-1127 Cell Rep
2211-1247
27760315
10.1016/j.celrep.2016.09.055
http://hdl.handle.net/10033/620588
Cell reports
ENG
http://creativecommons.org/licenses/by-nc-sa/4.0/
oai:repository.helmholtz-hzi.de:10033/6207502019-08-30T11:28:51Zcom_10033_56876col_10033_56896
Metabolic pathways in T cell activation and lineage differentiation.
Almeida, Luís
Lochner, Matthias
Berod, Luciana
Sparwasser, Tim
TwinCore, Centre for experimental and clinical infection research GmbH, Ferodor-Lynen-Str.7,30625 Hannover, Germany.
Recent advances in the field of immunometabolism support the concept that fundamental processes in T cell biology, such as TCR-mediated activation and T helper lineage differentiation, are closely linked to changes in the cellular metabolic programs. Although the major task of the intermediate metabolism is to provide the cell with a constant supply of energy and molecular precursors for the production of biomolecules, the dynamic regulation of metabolic pathways also plays an active role in shaping T cell responses. Key metabolic processes such as glycolysis, fatty acid and mitochondrial metabolism are now recognized as crucial players in T cell activation and differentiation, and their modulation can differentially affect the development of T helper cell lineages. In this review, we describe the diverse metabolic processes that T cells engage during their life cycle from naïve towards effector and memory T cells. We consider in particular how the cellular metabolism may actively support the function of T cells in their different states. Moreover, we discuss how molecular regulators such as mTOR or AMPK link environmental changes to adaptations in the cellular metabolism and elucidate the consequences on T cell differentiation and function.
2017-01-26T14:14:40Z
2017-01-26T14:14:40Z
2016-10
Article
Metabolic pathways in T cell activation and lineage differentiation. 2016, 28 (5):514-524 Semin. Immunol.
1096-3618
27825556
10.1016/j.smim.2016.10.009
http://hdl.handle.net/10033/620750
Seminars in immunology
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
oai:repository.helmholtz-hzi.de:10033/6208742019-08-30T11:34:48Zcom_10033_56876col_10033_56896
Metabolites: deciphering the molecular language between DCs and their environment.
Minarrieta, Lucía
Ghorbani, Peyman
Sparwasser, Tim
Berod, Luciana
Twincore Centre of Experimental and Clinical Infection Research; a joint venture between the Hannover Medical School and the Helmholtz Centre for Infection Research, Hannover 30625, Germany.
Dendritic cells (DCs) determine the outcome of the immune response based on signals they receive from the environment. Presentation of antigen under various contexts can lead to activation and differentiation of T cells for immunity or dampening of immune responses by establishing tolerance, primarily through the priming of regulatory T cells. Infections, inflammation and normal cellular interactions shape DC responses through direct contact or via cytokine signaling. Although it is widely accepted that DCs sense microbial components through pattern recognition receptors (PRRs), increasing evidence advocates for the existence of a set of signals that can profoundly shape DC function via PRR-independent pathways. This diverse group of host- or commensal-derived metabolites represents a newly appreciated code from which DCs can interpret environmental cues. In this review, we discuss the existing information on the effect of some of the most studied metabolites on DC function, together with the implications this may have in immune-mediated diseases.
2017-03-29T09:17:17Z
2017-03-29T09:17:17Z
2017-02
Article
Metabolites: deciphering the molecular language between DCs and their environment. 2017, 39 (2):177-198 Semin Immunopathol
1863-2300
27921148
10.1007/s00281-016-0609-6
http://hdl.handle.net/10033/620874
Seminars in immunopathology
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
oai:repository.helmholtz-hzi.de:10033/6209052019-08-30T11:36:04Zcom_10033_56876col_10033_56896
Development and Function of Secondary and Tertiary Lymphoid Organs in the Small Intestine and the Colon.
Buettner, Manuela
Lochner, Matthias
Twincore, Zentrum für experimentelle und klinische Infektionsforschung GmbH, Feodor-Lynen Str. 7, 30625 Hannover, Germany.
The immune system of the gut has evolved a number of specific lymphoid structures that contribute to homeostasis in the face of microbial colonization and food-derived antigenic challenge. These lymphoid organs encompass Peyer's patches (PP) in the small intestine and their colonic counterparts that develop in a programed fashion before birth. In addition, the gut harbors a network of lymphoid tissues that is commonly designated as solitary intestinal lymphoid tissues (SILT). In contrast to PP, SILT develop strictly after birth and consist of a dynamic continuum of structures ranging from small cryptopatches (CP) to large, mature isolated lymphoid follicles (ILF). Although the development of PP and SILT follow similar principles, such as an early clustering of lymphoid tissue inducer (LTi) cells and the requirement for lymphotoxin beta (LTβ) receptor-mediated signaling, the formation of CP and their further maturation into ILF is associated with additional intrinsic and environmental signals. Moreover, recent data also indicate that specific differences exist in the regulation of ILF formation between the small intestine and the colon. Importantly, intestinal inflammation in both mice and humans is associated with a strong expansion of the lymphoid network in the gut. Recent experiments in mice suggest that these structures, although they resemble large, mature ILF in appearance, may represent de novo-induced tertiary lymphoid organs (TLO). While, so far, it is not clear whether intestinal TLO contribute to the exacerbation of inflammatory pathology, it has been shown that ILF provide the critical microenvironment necessary for the induction of an effective host response upon infection with enteric bacterial pathogens. Regarding the importance of ILF for intestinal immunity, interfering with the development and maturation of these lymphoid tissues may offer novel means for manipulating the immune response during intestinal infection or inflammation.
2017-05-03T13:54:22Z
2017-05-03T13:54:22Z
2016
Article
Development and Function of Secondary and Tertiary Lymphoid Organs in the Small Intestine and the Colon. 2016, 7:342 Front Immunol
27656182
10.3389/fimmu.2016.00342
http://hdl.handle.net/10033/620905
Frontiers in immunology
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
oai:repository.helmholtz-hzi.de:10033/6209112019-08-30T11:33:05Zcom_10033_56876col_10033_56896
Melanocortin-1 receptor activation is neuroprotective in mouse models of neuroinflammatory disease.
Mykicki, Nadine
Herrmann, Alexander M
Schwab, Nicholas
Deenen, René
Sparwasser, Tim
Limmer, Andreas
Wachsmuth, Lydia
Klotz, Luisa
Köhrer, Karl
Faber, Cornelius
Wiendl, Heinz
Luger, Thomas A
Meuth, Sven G
Loser, Karin
TWINCORE; Zentrum für experimentelle und klinische Infectionsforsching GmbH, Feodor-Lynen Str. 17, 30625 Hannover, Germany.
In inflammation-associated progressive neuroinflammatory disorders, such as multiple sclerosis (MS), inflammatory infiltrates containing T helper 1 (TH1) and TH17 cells cause demyelination and neuronal degeneration. Regulatory T cells (Treg) control the activation and infiltration of autoreactive T cells into the central nervous system (CNS). In MS and experimental autoimmune encephalomyelitis (EAE) in mice, Treg function is impaired. We show that a recently approved drug, Nle(4)-d-Phe(7)-α-melanocyte-stimulating hormone (NDP-MSH), induced functional Treg, resulting in amelioration of EAE progression in mice. NDP-MSH also prevented immune cell infiltration into the CNS by restoring the integrity of the blood-brain barrier. NDP-MSH exerted long-lasting neuroprotective effects in mice with EAE and prevented excitotoxic death and reestablished action potential firing in mouse and human neurons in vitro. Neuroprotection by NDP-MSH was mediated via signaling through the melanocortin-1 and orphan nuclear 4 receptors in mouse and human neurons. NDP-MSH may be of benefit in treating neuroinflammatory diseases such as relapsing-remitting MS and related disorders.
2017-05-08T12:21:56Z
2017-05-08T12:21:56Z
2016-10-26
Article
Melanocortin-1 receptor activation is neuroprotective in mouse models of neuroinflammatory disease. 2016, 8 (362):362ra146 Sci Transl Med
1946-6242
27797962
10.1126/scitranslmed.aaf8732
http://hdl.handle.net/10033/620911
Science translational medicine
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
oai:repository.helmholtz-hzi.de:10033/6209442019-08-30T11:33:57Zcom_10033_56876com_10033_621723col_10033_621724col_10033_56896
MyD88 signaling in dendritic cells and the intestinal epithelium controls immunity against intestinal infection with C. rodentium.
Friedrich, Christin
Mamareli, Panagiota
Thiemann, Sophie
Kruse, Friederike
Wang, Zuobai
Holzmann, Bernhard
Strowig, Till
Sparwasser, Tim
Lochner, Matthias
TWINCORE, Zentrum für experimentelle und klinische Infektionsforschung GmbH, Feodor-Lynen Str.7, 30625 Hannover, Germany.
MyD88-mediated signaling downstream of Toll-like receptors and the IL-1 receptor family is critically involved in the induction of protective host responses upon infections. Although it is known that MyD88-deficient mice are highly susceptible to a wide range of bacterial infections, the cell type-specific contribution of MyD88 in protecting the host against intestinal bacterial infection is only poorly understood. In order to investigate the importance of MyD88 in specific immune and nonimmune cell types during intestinal infection, we employed a novel murine knock-in model for MyD88 that enables the cell type-specific reactivation of functional MyD88 expression in otherwise MyD88-deficient mice. We report here that functional MyD88 signaling in CD11c+ cells was sufficient to activate intestinal dendritic cells (DC) and to induce the early group 3 innate lymphoid cell (ILC3) response as well as the development of colonic Th17/Th1 cells in response to infection with the intestinal pathogen C. rodentium. In contrast, restricting MyD88 signaling to several other cell types, including macrophages (MO), T cells or ILC3 did not induce efficient intestinal immune responses upon infection. However, we observed that the functional expression of MyD88 in intestinal epithelial cells (IEC) also partially protected the mice during intestinal infection, which was associated with enhanced epithelial barrier integrity and increased expression of the antimicrobial peptide RegIIIγ and the acute phase protein SAA1 by epithelial cells. Together, our data suggest that MyD88 signaling in DC and IEC is both essential and sufficient to induce a full spectrum of host responses upon intestinal infection with C. rodentium.
2017-06-14T13:29:19Z
2017-06-14T13:29:19Z
2017-05
Article
MyD88 signaling in dendritic cells and the intestinal epithelium controls immunity against intestinal infection with C. rodentium. 2017, 13 (5):e1006357 PLoS Pathog.
1553-7374
28520792
10.1371/journal.ppat.1006357
http://hdl.handle.net/10033/620944
PLoS pathogens
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
oai:repository.helmholtz-hzi.de:10033/6209752019-08-30T11:36:05Zcom_10033_56876com_10033_620652col_10033_620673col_10033_56896
IL-33/ST2 pathway drives regulatory T cell dependent suppression of liver damage upon cytomegalovirus infection.
Popovic, Branka
Golemac, Mijo
Podlech, Jürgen
Zeleznjak, Jelena
Bilic-Zulle, Lidija
Lukic, Miodrag L
Cicin-Sain, Luka
Reddehase, Matthias J
Sparwasser, Tim
Krmpotic, Astrid
Jonjic, Stipan
TWINCORE, Zentrum für experimentelle und klinische Infektionsforschung GmbH, Feodor-Lynen Str.7, 30625 Hannover, Germany.
Regulatory T (Treg) cells dampen an exaggerated immune response to viral infections in order to avoid immunopathology. Cytomegaloviruses (CMVs) are herpesviruses usually causing asymptomatic infection in immunocompetent hosts and induce strong cellular immunity which provides protection against CMV disease. It remains unclear how these persistent viruses manage to avoid induction of immunopathology not only during the acute infection but also during life-long persistence and virus reactivation. This may be due to numerous viral immunoevasion strategies used to specifically modulate immune responses but also induction of Treg cells by CMV infection. Here we demonstrate that liver Treg cells are strongly induced in mice infected with murine CMV (MCMV). The depletion of Treg cells results in severe hepatitis and liver damage without alterations in the virus load. Moreover, liver Treg cells show a high expression of ST2, a cellular receptor for tissue alarmin IL-33, which is strongly upregulated in the liver of infected mice. We demonstrated that IL-33 signaling is crucial for Treg cell accumulation after MCMV infection and ST2-deficient mice show a more pronounced liver pathology and higher mortality compared to infected control mice. These results illustrate the importance of IL-33 in the suppressive function of liver Treg cells during CMV infection.
2017-06-22T12:40:02Z
2017-06-22T12:40:02Z
2017-04
Article
IL-33/ST2 pathway drives regulatory T cell dependent suppression of liver damage upon cytomegalovirus infection. 2017, 13 (4):e1006345 PLoS Pathog.
1553-7374
28448566
10.1371/journal.ppat.1006345
http://hdl.handle.net/10033/620975
PLoS pathogens
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
oai:repository.helmholtz-hzi.de:10033/6209862019-08-30T11:26:42Zcom_10033_56876col_10033_56896
The human cytomegalovirus glycoprotein pUL11 acts via CD45 to induce T cell IL-10 secretion.
Zischke, Jasmin
Mamareli, Panagiota
Pokoyski, Claudia
Gabaev, Ildar
Buyny, Sabine
Jacobs, Roland
Falk, Christine S
Lochner, Matthias
Sparwasser, Tim
Schulz, Thomas F
Kay-Fedorov, Penelope C
TWINCORE, Zentrum für experimentelle und klinische Infectionsforschung GmbH, Feodor-Lynen-Str. 7, 30625 Hannover, Germany.
Human Cytomegalovirus (HCMV) is a widespread pathogen, infection with which can cause severe disease for immunocompromised individuals. The complex changes wrought on the host's immune system during both productive and latent HCMV infection are well known. Infected cells are masked and manipulated and uninfected immune cells are also affected; peripheral blood mononuclear cell (PBMC) proliferation is reduced and cytokine profiles altered. Levels increase of the anti-inflammatory cytokine IL-10, which may be important for the establishment of HCMV infections and is required for the development of high viral titres by murine cytomegalovirus. The mechanisms by which HCMV affects T cell IL-10 secretion are not understood. We show here that treatment of PBMC with purified pUL11 induces IL-10 producing T cells as a result of pUL11 binding to the CD45 phosphatase on T cells. IL-10 production induced by HCMV infection is also in part mediated by pUL11. Supernatants from pUL11 treated cells have anti-inflammatory effects on untreated PBMC. Considering the mechanism, CD45 can be a positive or negative regulator of TCR signalling, depending on its expression level, and we show that pUL11 also has concentration dependent activating or inhibitory effects on T cell proliferation and on the kinase function of the CD45 substrate Lck. pUL11 is therefore the first example of a viral protein that can target CD45 to induce T cells with anti-inflammatory properties. It is also the first HCMV protein shown to induce T cell IL-10 secretion. Understanding the mechanisms by which pUL11-induced changes in signal strength influence T cell development and function may provide the basis for the development of novel antiviral treatments and therapies against immune pathologies.
2017-07-04T13:09:31Z
2017-07-04T13:09:31Z
2017-06
Article
The human cytomegalovirus glycoprotein pUL11 acts via CD45 to induce T cell IL-10 secretion. 2017, 13 (6):e1006454 PLoS Pathog.
1553-7374
28628650
10.1371/journal.ppat.1006454
http://hdl.handle.net/10033/620986
PLoS pathogens
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
oai:repository.helmholtz-hzi.de:10033/6210352019-08-30T11:36:32Zcom_10033_56876col_10033_56896
Tregs restrain dendritic cell autophagy to ameliorate autoimmunity.
Alissafi, Themis
Banos, Aggelos
Boon, Louis
Sparwasser, Tim
Ghigo, Alessandra
Wing, Kajsa
Vassilopoulos, Dimitrios
Boumpas, Dimitrios
Chavakis, Triantafyllos
Cadwell, Ken
Verginis, Panayotis
TWINCORE, Zentrum für experimentelle und klinische Infektionsforschung GmbH, Feodor-Lynnen Str. 7,30625 Hannover, Germany.
Design of efficacious Treg-based therapies and establishment of clinical tolerance in autoimmune diseases have proven to be challenging. The clinical implementation of Treg immunotherapy has been hampered by various impediments related to the stability and isolation procedures of Tregs as well as the specific in vivo targets of Treg modalities. Herein, we have demonstrated that Foxp3+ Tregs potently suppress autoimmune responses in vivo through inhibition of the autophagic machinery in DCs in a cytotoxic T-lymphocyte-associated protein 4-dependent (CTLA4-dependent) manner. Autophagy-deficient DCs exhibited reduced immunogenic potential and failed to prime autoantigen-specific CD4+ T cells to mediate autoimmunity. Mechanistically, CTLA4 binding promoted activation of the PI3K/Akt/mTOR axis and FoxO1 nuclear exclusion in DCs, leading to decreased transcription of the autophagy component microtubule-associated protein 1 light chain 3β (Lc3b). Human DCs treated with CTLA4-Ig, a fusion protein composed of the Fc region of IgG1 and the extracellular domain of CTLA4 (also known as abatacept, marketed as Orencia), demonstrated reduced levels of autophagosome formation, while DCs from CTLA4-Ig-treated rheumatoid arthritis patients displayed diminished LC3B transcripts. Collectively, our data identify the canonical autophagy pathway in DCs as a molecular target of Foxp3+ Treg-mediated suppression that leads to amelioration of autoimmune responses. These findings may pave the way for the development of therapeutic protocols that exploit Tregs for the treatment of autoimmunity as well as diseases in which disturbed tolerance is a common denominator.
2017-08-02T13:32:42Z
2017-08-02T13:32:42Z
2017-06-30
Article
Tregs restrain dendritic cell autophagy to ameliorate autoimmunity. 2017, 127 (7):2789-2804 J. Clin. Invest.
1558-8238
28581446
10.1172/JCI92079
http://hdl.handle.net/10033/621035
The Journal of clinical investigation
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
oai:repository.helmholtz-hzi.de:10033/6211442019-08-30T11:27:16Zcom_10033_56876col_10033_56896
Schistosome-induced pulmonary B cells inhibit allergic airway inflammation and display a reduced Th2-driving function.
van der Vlugt, L E P M
Obieglo, K
Ozir-Fazalalikhan, A
Sparwasser, Tim
Haeberlein, S
Smits, H H
TwinCore, Zentrum für experimentelle und klinische Infektionsforschung GmbH, Feodor-Lynen-Str. 7, 30625 Hannover, Germany.
Chronic schistosome infections protect against allergic airway inflammation (AAI) via the induction of IL-10-producing splenic regulatory B (Breg) cells. Previous experiments have demonstrated that schistosome-induced pulmonary B cells can also reduce AAI, but act independently of IL-10. We have now further characterized the phenotype and inhibitory activity of these protective pulmonary B cells. We excluded a role for regulatory T (Treg) cell induction as putative AAI-protective mechanisms. Schistosome-induced B cells showed increased CD86 expression and reduced cytokine expression in response to Toll-like receptor (TLR) ligands compared with control B cells. To investigate the consequences for T cell activation we cultured ovalbumin (OVA)-pulsed, schistosome-induced B cells with OVA-specific transgenic T cells and observed less Th2 cytokine expression and T cell proliferation compared with control conditions. This suppressive effect was preserved even under optimal T cell stimulation by anti-CD3/28. Blocking of the inhibitory cytokines IL-10 or TGF-β only marginally restored Th2 cytokine induction. These data suggest that schistosome-induced pulmonary B cells are impaired in their capacity to produce cytokines to TLR ligands and to induce Th2 cytokine responses independent of their antigen-presenting function. These findings underline the presence of distinct B cell subsets with different stimulatory or inhibitory properties even if induced by the same type of helminth.
2017-10-24T09:26:47Z
2017-10-24T09:26:47Z
2017-08
Article
Schistosome-induced pulmonary B cells inhibit allergic airway inflammation and display a reduced Th2-driving function. 2017, 47 (9):545-554 Int. J. Parasitol.
1879-0135
28385494
10.1016/j.ijpara.2017.02.002
http://hdl.handle.net/10033/621144
International journal for parasitology
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
oai:repository.helmholtz-hzi.de:10033/6211672019-08-30T11:25:43Zcom_10033_56876col_10033_56896
TLR3 is required for survival following Coxsackievirus B3 infection by driving T lymphocyte activation and polarization: The role of dendritic cells.
Sesti-Costa, Renata
Françozo, Marcela Cristina Santiago
Silva, Grace Kelly
Proenca-Modena, José Luiz
Silva, João Santana
Zentrum für experimentelle und klinische Infektionsforschung GmbH, Feodor-Lynen-Str.7, 30625 Hannover, Germany.
Adoptive Transfer
Animals
CD4-Positive T-Lymphocytes
Coxsackievirus Infections
Cytokines
Dendritic Cells
Enterovirus B, Human
Lymphocyte Activation
Mice
Mice, Knockout
Toll-Like Receptor 3
Type B coxsackievirus (CVB) is a common cause of acute and chronic myocarditis, meningitis and pancreatitis, often leading to heart failure and pancreatic deficiency. The polarization of CD4+ T lymphocytes and their cytokine milieu are key factors in the outcome of CVB-induced diseases. Thus, sensing the virus and driving the adaptive immune response are essential for the establishment of a protective immune response. TLR3 is a crucial virus recognition receptor that confers the host with resistance to CVB infection. In the current study, we found that TLR3 expression in dendritic cells plays a role in their activation upon CVB3 infection in vitro, as TLR3-deficient dendritic cells up-regulate CD80 and CD86 to a less degree than WT cells. Instead, they up-regulated the inhibitory molecule PD-L1 and secreted considerably lower levels of TNF-α and IL-10 and a higher level of IL-23. T lymphocyte proliferation in co-culture with CVB3-infected dendritic cells was increased by TLR3-expressing DCs and other cells. Furthermore, in the absence of TLR3, the T lymphocyte response was shifted toward a Th17 profile, which was previously reported to be deleterious for the host. TLR3-deficient mice were very susceptible to CVB3 infection, with increased pancreatic injury and extensive inflammatory infiltrate in the heart that was associated with uncontrolled viral replication. Adoptive transfer of TLR3+ dendritic cells slightly improved the survival of TLR-deficient mice following CVB3 infection. Therefore, our findings highlight the importance of TLR3 signaling in DCs and in other cells to induce activation and polarization of the CD4+ T lymphocyte response toward a Th1 profile and consequently for a better outcome of CVB3 infection. These data provide new insight into the immune-mediated mechanisms by which CVBs are recognized and cleared in order to prevent the development of myocarditis and pancreatitis and may contribute to the design of therapies for enteroviral infections.
2017-11-07T15:00:37Z
2017-11-07T15:00:37Z
2017
Article
TLR3 is required for survival following Coxsackievirus B3 infection by driving T lymphocyte activation and polarization: The role of dendritic cells. 2017, 12 (10):e0185819 PLoS ONE
1932-6203
28973047
10.1371/journal.pone.0185819
http://hdl.handle.net/10033/621167
PloS one
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
oai:repository.helmholtz-hzi.de:10033/6211722019-08-30T11:34:43Zcom_10033_56876col_10033_56896
About cytokeratin 19 and the drivers of liver regeneration.
Junge, Norman
Sharma, Amar Deep
Ott, Michael
TwinCore, Zentrum für experimentelle und klinische Infektionsforschung GmbH, Feodor-Lynen Str. 7, 30625 Hannover, Germany.
2017-11-13T15:17:50Z
2017-11-13T15:17:50Z
2017-10-12
Article
About cytokeratin 19 and the drivers of liver regeneration. 2017 J. Hepatol.
1600-0641
29031907
10.1016/j.jhep.2017.10.003
http://hdl.handle.net/10033/621172
Journal of hepatology
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
oai:repository.helmholtz-hzi.de:10033/6211912019-08-30T11:25:11Zcom_10033_56876col_10033_56896
Suppression of Th17-polarized airway inflammation by rapamycin.
Joean, Oana
Hueber, Anja
Feller, Felix
Jirmo, Adan Chari
Lochner, Matthias
Dittrich, Anna-Maria
Albrecht, Melanie
TWINCORE, Zentrum für experimentelle und kliische Infektionsforschung GmbH, Deodor-Lynen-Sr. 7, 30625 Hannover, Germany.
Because Th17-polarized airway inflammation correlates with poor control in bronchial asthma and is a feature of numerous other difficult-to-treat inflammatory lung diseases, new therapeutic approaches for this type of airway inflammation are necessary. We assessed different licensed anti-inflammatory agents with known or expected efficacy against Th17-polarization in mouse models of Th17-dependent airway inflammation. Upon intravenous transfer of in vitro derived Th17 cells and intranasal challenge with the corresponding antigen, we established acute and chronic murine models of Th17-polarised airway inflammation. Consecutively, we assessed the efficacy of methylprednisolone, roflumilast, azithromycin, AM80 and rapamycin against acute or chronic Th17-dependent airway inflammation. Quantifiers for Th17-associated inflammation comprised: bronchoalveolar lavage (BAL) differential cell counts, allergen-specific cytokine and immunoglobulin secretion, as well as flow cytometric phenotyping of pulmonary inflammatory cells. Only rapamycin proved effective against acute Th17-dependent airway inflammation, accompanied by increased plasmacytoid dendritic cells (pDCs) and reduced neutrophils as well as reduced CXCL-1 levels in BAL. Chronic Th17-dependent airway inflammation was unaltered by rapamycin treatment. None of the other agents showed efficacy in our models. Our results demonstrate that Th17-dependent airway inflammation is difficult to treat with known agents. However, we identify rapamycin as an agent with inhibitory potential against acute Th17-polarized airway inflammation.
2017-12-01T13:08:06Z
2017-12-01T13:08:06Z
2017-11-10
Article
Suppression of Th17-polarized airway inflammation by rapamycin. 2017, 7 (1):15336 Sci Rep
2045-2322
29127369
10.1038/s41598-017-15750-6
http://hdl.handle.net/10033/621191
Scientific reports
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
oai:repository.helmholtz-hzi.de:10033/6211972019-08-30T11:25:11Zcom_10033_56876col_10033_56896
Adenoviral vector-mediated GM-CSF gene transfer improves anti-mycobacterial immunity in mice - role of regulatory T cells.
Singpiel, Alena
Kramer, Julia
Maus, Regina
Stolper, Jennifer
Bittersohl, Lara Friederike
Gauldie, Jack
Kolb, Martin
Welte, Tobias
Sparwasser, Tim
Maus, Ulrich A
TWINCORE; Zentrum für experimentelle und klinische Infektionsforschung GmbH, Feodor-Lynen-Str. 7, 30625 Hannover, Germany.
Granulocyte macrophage-colony stimulating factor (GM-CSF) is a hematopoietic growth factor involved in differentiation, survival and activation of myeloid and non-myeloid cells with important implications for lung antibacterial immunity. Here we examined the effect of pulmonary adenoviral vector-mediated delivery of GM-CSF (AdGM-CSF) on anti-mycobacterial immunity in M. bovis BCG infected mice. Exposure of M. bovis BCG infected mice to AdGM-CSF either applied on 6h, or 6h and 7days post-infection substantially increased alveolar recruitment of iNOS and IL-12 expressing macrophages, and significantly increased accumulation of IFNγpos T cells and particularly regulatory T cells (Tregs). This was accompanied by significantly reduced mycobacterial loads in the lungs of mice. Importantly, diphtheria toxin-induced depletion of Tregs did not influence mycobacterial loads, but accentuated immunopathology in AdGM-CSF-exposed mice infected with M. bovis BCG. Together, the data demonstrate that AdGM-CSF therapy improves lung protective immunity against M. bovis BCG infection in mice independent of co-recruited Tregs, which however critically contribute to limit lung immunopathology in BCG-infected mice. These data may be relevant to the development of immunomodulatory strategies to limit immunopathology-based lung injury in tuberculosis in humans.
2017-12-07T09:02:28Z
2017-12-07T09:02:28Z
2017-10-26
Article
Adenoviral vector-mediated GM-CSF gene transfer improves anti-mycobacterial immunity in mice - role of regulatory T cells. 2017 Immunobiology
1878-3279
29089144
10.1016/j.imbio.2017.10.042
http://hdl.handle.net/10033/621197
Immunobiology
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
oai:repository.helmholtz-hzi.de:10033/6212482019-08-30T11:25:43Zcom_10033_56876col_10033_56896
Regulatory T Cells Suppress Inflammation and Blistering in Pemphigoid Diseases.
Bieber, Katja
Sun, Shijie
Witte, Mareike
Kasprick, Anika
Beltsiou, Foteini
Behnen, Martina
Laskay, Tamás
Schulze, Franziska S
Pipi, Elena
Reichhelm, Niklas
Pagel, René
Zillikens, Detlef
Schmidt, Enno
Sparwasser, Tim
Kalies, Kathrin
Ludwig, Ralf J
TWINCORE, Zentrum für experimentelle und klinische Infektionsforschung GmbH, Feodor-Lynen-Str.7, 30625 Hannover, Germany.
Regulatory T cells (Tregs) are well known for their modulatory functions in adaptive immunity. Through regulation of T cell functions, Tregs have also been demonstrated to indirectly curb myeloid cell-driven inflammation. However, direct effects of Tregs on myeloid cell functions are insufficiently characterized, especially in the context of myeloid cell-mediated diseases, such as pemphigoid diseases (PDs). PDs are caused by autoantibodies targeting structural proteins of the skin. Autoantibody binding triggers myeloid cell activation through specific activation of Fc gamma receptors, leading to skin inflammation and subepidermal blistering. Here, we used mouse models to address the potential contribution of Tregs to PD pathogenesis in vivo. Depletion of Tregs induced excessive inflammation and blistering both clinically and histologically in two different PD mouse models. Of note, in the skin of Treg-depleted mice with PD, we detected increased expression of different cytokines, including Th2-specific IL-4, IL-10, and IL-13 as well as pro-inflammatory Th1 cytokine IFN-γ and the T cell chemoattractant CXCL-9. We next aimed to determine whether Tregs alter the migratory behavior of myeloid cells, dampen immune complex (IC)-induced myeloid cell activation, or both. In vitro experiments demonstrated that co-incubation of IC-activated myeloid cells with Tregs had no impact on the release of reactive oxygen species (ROS) but downregulated β2 integrin expression. Hence, Tregs mitigate PD by altering the migratory capabilities of myeloid cells rather than their release of ROS. Modulating cytokine expression by administering an excess of IL-10 or blocking IFN-γ may be used in clinical translation of these findings.
2018-01-23T14:11:28Z
2018-01-23T14:11:28Z
2017
Article
Regulatory T Cells Suppress Inflammation and Blistering in Pemphigoid Diseases. 2017, 8:1628 Front Immunol
1664-3224
29225603
10.3389/fimmu.2017.01628
http://hdl.handle.net/10033/621248
Frontiers in immunology
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
oai:repository.helmholtz-hzi.de:10033/6213252019-08-30T11:28:24Zcom_10033_56876col_10033_56896
In situ generation, metabolism and immunomodulatory signaling actions of nitro-conjugated linoleic acid in a murine model of inflammation.
Villacorta, Luis
Minarrieta, Lucia
Salvatore, Sonia R
Khoo, Nicholas K
Rom, Oren
Gao, Zhen
Berman, Rebecca C
Jobbagy, Soma
Li, Lihua
Woodcock, Steven R
Chen, Y Eugene
Freeman, Bruce A
Ferreira, Ana M
Schopfer, Francisco J
Vitturi, Dario A
TWINCORE, Zentrum für experimentelle und klinischeInfektionsforschung GmbH, Feodor-Lynen-Str. 7, 30625 Hannover, Germany.
Conjugated linoleic acid (CLA) is a prime substrate for intra-gastric nitration giving rise to the formation of nitro-conjugated linoleic acid (NO2-CLA). Herein, NO2-CLA generation is demonstrated within the context of acute inflammatory responses both in vitro and in vivo. Macrophage activation resulted in dose- and time-dependent CLA nitration and also in the production of secondary electrophilic and non-electrophilic derivatives. Both exogenous NO2-CLA as well as that generated in situ, attenuated NF-κB-dependent gene expression, decreased pro-inflammatory cytokine production and up-regulated Nrf2-regulated proteins. Importantly, both CLA nitration and the corresponding downstream anti-inflammatory actions of NO2-CLA were recapitulated in a mouse peritonitis model where NO2-CLA administration decreased pro-inflammatory cytokines and inhibited leukocyte recruitment. Taken together, our results demonstrate that the formation of NO2-CLA has the potential to function as an adaptive response capable of not only modulating inflammation amplitude but also protecting neighboring tissues via the expression of Nrf2-dependent genes.
2018-03-19T15:56:35Z
2018-03-19T15:56:35Z
2018-05
Article
In situ generation, metabolism and immunomodulatory signaling actions of nitro-conjugated linoleic acid in a murine model of inflammation. 2018, 15:522-531 Redox Biol
2213-2317
29413964
10.1016/j.redox.2018.01.005
http://hdl.handle.net/10033/621325
Redox biology
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
oai:repository.helmholtz-hzi.de:10033/6213542019-08-30T11:35:13Zcom_10033_56876col_10033_56896
Proceedings of the signature series event of the international society for cellular therapy: "Advancements in cellular therapies and regenerative medicine in digestive diseases," London, United Kingdom, May 3, 2017.
Ciccocioppo, Rachele
Dos Santos, Claudia C
Baumgart, Daniel C
Cangemi, Giuseppina C
Cardinale, Vincenzo
Ciacci, Carolina
De Coppi, Paolo
Haldar, Debashis
Klersy, Catherine
Nostro, M Cristina
Ott, Michael
Piemonti, Lorenzo
Tomei, Alice A
Uygun, Basak
Vetrano, Stefania
Orlando, Giuseppe
A summary of the First Signature Series Event, "Advancements in Cellular Therapies and Regenerative Medicine for Digestive Diseases," held on May 3, 2017, in London, United Kingdom, is presented. Twelve speakers from three continents covered major topics in the areas of cellular therapy and regenerative medicine applied to liver and gastrointestinal medicine as well as to diabetes mellitus. Highlights from their presentations, together with an overview of the global impact of digestive diseases and a proposal for a shared online collection and data-monitoring platform tool, are included in this proceedings. Although growing evidence demonstrate the feasibility and safety of exploiting cell-based technologies for the treatment of digestive diseases, regulatory and methodological obstacles will need to be overcome before the successful implementation in the clinic of these novel attractive therapeutic strategies.
2018-04-13T11:14:48Z
2018-04-13T11:14:48Z
2018-03
Proceedings of the signature series event of the international society for cellular therapy: "Advancements in cellular therapies and regenerative medicine in digestive diseases," London, United Kingdom, May 3, 2017. 2018, 20 (3):461-476 Cytotherapy
1477-2566
29398624
10.1016/j.jcyt.2017.12.004
http://hdl.handle.net/10033/621354
Cytotherapy
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
oai:repository.helmholtz-hzi.de:10033/6214002019-08-30T11:25:06Zcom_10033_56876col_10033_56896
Regulatory T cells control endothelial chemokine production and migration of T cells into intestinal tumors of APC mice.
Akeus, Paulina
Szeponik, Louis
Ahlmanner, Filip
Sundström, Patrik
Alsén, Samuel
Gustavsson, Bengt
Sparwasser, Tim
Raghavan, Sukanya
Quiding-Järbrink, Marianne
TWINCORE, Zentrum für experimentelle uns klinische Ifektionsforschung GmbH, Feodor-Lynen-Str. 7, 30625 Hannover, Germany.
APCmin/+
CXCR3
Colon cancer
Migration
Regulatory T cells
Tumor-infiltrating lymphocytes are crucial for anti-tumor immunity. We have previously shown that regulatory T cells (Treg) are able to reduce T-cell transendothelial migration in vitro and accumulation of effector T cells in intestinal tumors in vivo. Treg depletion also resulted in increased levels of the chemokines CXCL9 and CXCL10 specifically in the tumors. In this study, we investigated the mechanisms for Treg mediated suppression of T-cell migration into intestinal tumors in the APC
2018-06-18T08:17:07Z
2018-06-18T08:17:07Z
2018-04-18
Article
1432-0851
29671006
10.1007/s00262-018-2161-9
http://hdl.handle.net/10033/621400
Attribution-NonCommercial-ShareAlike 3.0 United States
http://creativecommons.org/licenses/by-nc-sa/3.0/us/
Cancer immunology, immunotherapy : CII
oai:repository.helmholtz-hzi.de:10033/6214032019-08-30T11:29:44Zcom_10033_56876col_10033_56896
Cytokines, Antibodies, and Histopathological Profiles during Giardia Infection and Variant-Specific Surface Protein-Based Vaccination.
Serradell, Marianela C
Gargantini, Pablo R
Saura, Alicia
Oms, Sergio R
Rupil, Lucía L
Berod, Luciana
Sparwasser, Tim
Luján, Hugo D
TWINCORE, Zentrum für experimentelle und klinischeInfektionsforschung GmbH, Feodor-Lynen-Str. 7, 30625 Hannover, Germany.
animal models
cytokines
giardiasis
immunization
Giardiasis is one of the most common human intestinal diseases worldwide. Several experimental animal models have been used to evaluate
2018-06-18T13:10:16Z
2018-06-18T13:10:16Z
2018-06-01
Article
1098-5522
29555679
10.1128/IAI.00773-17
http://hdl.handle.net/10033/621403
Attribution-NonCommercial-ShareAlike 3.0 United States
http://creativecommons.org/licenses/by-nc-sa/3.0/us/
Infection and immunity
oai:repository.helmholtz-hzi.de:10033/6214332019-08-30T11:31:46Zcom_10033_56876col_10033_56896
Fatty acid metabolism in CD8 T cell memory: Challenging current concepts.
Raud, Brenda
McGuire, Peter J
Jones, Russell G
Sparwasser, Tim
Berod, Luciana
TWINCORE, Zentrum für experimentelle und klinischeInfektionsforschung GmbH, Feodor-Lynen-Str. 7, 30625 Hannover, Germany.
CPT
Keywordscarnitine palmitoyltransferase
T cells
etomoxir
fatty acid oxidation
memory
CD8
2018-07-31T13:57:06Z
2018-07-31T13:57:06Z
2018-05-01
Article
1600-065X
29664569
10.1111/imr.12655
http://hdl.handle.net/10033/621433
Attribution-NonCommercial-ShareAlike 3.0 United States
http://creativecommons.org/licenses/by-nc-sa/3.0/us/
Immunological reviews
oai:repository.helmholtz-hzi.de:10033/6214942019-08-30T11:30:31Zcom_10033_56876col_10033_56896
Varicella zoster virus infections in neurological patients: a clinical study.
Skripuletz, Thomas
Pars, Kaweh
Schulte, Alina
Schwenkenbecher, Philipp
Yildiz, Özlem
Ganzenmueller, Tina
Kuhn, Maike
Spreer, Annette
Wurster, Ulrich
Pul, Refik
Stangel, Martin
Sühs, Kurt-Wolfram
Trebst, Corinna
TWINCORE, Zentrum für experimentelle und klinischeInfektionsforschung GmbH, Feodor-Lynen-Str. 7, 30625 Hannover, Germany.
CNS
Cerebrospinal fluid
Herpes zoster
VZV
Varicella zoster virus (VZV) reactivation is a common infectious disease in neurology and VZV the second most frequent virus detected in encephalitis. This study investigated characteristics of clinical and laboratory features in patients with VZV infection. Two hundred eighty two patients with VZV reactivation that were hospitalized in the department of neurology in the time from 2005 to 2013 were retrospectively evaluated. Results from cerebrospinal fluid (CSF) analysis were available from 85 patients. Trigeminal rash was the most common clinical manifestation, followed by segmental rash, CNS infection, facial nerve palsy, postherpetic neuralgia, and radiculitis. MRI of the brain performed in 25/33 patients with encephalitis/meningitis did not show any signs of infection in the brain parenchyma. Only one patient showed contrast enhancement in the hypoglossal nerve. General signs of infection such as fever or elevated CRP values were found in only half of the patients. Furthermore, rash was absent in a quarter of patients with CNS infection and facial nerve palsy, and thus, infection could only be proven by CSF analysis. Although slight inflammatory CSF changes occurred in few patients with isolated rash, the frequency was clearly higher in patients with CNS infection and facial nerve palsy. Monosegmental herpes zoster is often uncomplicated and a diagnostic lumbar puncture is not essential. In contrast, CSF analysis is an essential diagnostic tool in patients with skin lesions and cranial nerve or CNS affection. In patients with neuro-psychiatric symptoms and inflammatory CSF changes analysis for VZV should be performed even in the absence of skin lesions.
2018-09-25T12:59:18Z
2018-09-25T12:59:18Z
2018-05-25
Article
1471-2334
29801466
10.1186/s12879-018-3137-2
http://hdl.handle.net/10033/621494
Attribution-NonCommercial-ShareAlike 3.0 United States
http://creativecommons.org/licenses/by-nc-sa/3.0/us/
BMC infectious diseases
oai:repository.helmholtz-hzi.de:10033/6215892019-08-30T11:29:44Zcom_10033_56876com_10033_620652col_10033_620675col_10033_56896
De Novo Fatty Acid Synthesis During Mycobacterial Infection Is a Prerequisite for the Function of Highly Proliferative T Cells, But Not for Dendritic Cells or Macrophages.
Stüve, Philipp
Minarrieta, Lucía
Erdmann, Hanna
Arnold-Schrauf, Catharina
Swallow, Maxine
Guderian, Melanie
Krull, Freyja
Hölscher, Alexandra
Ghorbani, Peyman
Behrends, Jochen
Abraham, Wolf-Rainer
Hölscher, Christoph
Sparwasser, Tim D
Berod, Luciana
TWINCORE, Zentrum für experimentelle und klinische Infektionsforschung GmbH,Feodor-Lynen Str. 7, 30625 Hannover, Germany.
Mycobacterium bovis BCG
Mycobacterium tuberculosis
acetyl-CoA carboxylase 1
acetyl-CoA carboxylase 2
dendritic cells
fatty acid oxidation
fatty acid synthesis
macrophages
Mycobacterium tuberculosis (Mtb), the causative agent of human tuberculosis, is able to efficiently manipulate the host immune system establishing chronic infection, yet the underlying mechanisms of immune evasion are not fully understood. Evidence suggests that this pathogen interferes with host cell lipid metabolism to ensure its persistence. Fatty acid metabolism is regulated by acetyl-CoA carboxylase (ACC) 1 and 2; both isoforms catalyze the conversion of acetyl-CoA into malonyl-CoA, but have distinct roles. ACC1 is located in the cytosol, where it regulates de novo fatty acid synthesis (FAS), while ACC2 is associated with the outer mitochondrial membrane, regulating fatty acid oxidation (FAO). In macrophages, mycobacteria induce metabolic changes that lead to the cytosolic accumulation of lipids. This reprogramming impairs macrophage activation and contributes to chronic infection. In dendritic cells (DCs), FAS has been suggested to underlie optimal cytokine production and antigen presentation, but little is known about the metabolic changes occurring in DCs upon mycobacterial infection and how they affect the outcome of the immune response. We therefore determined the role of fatty acid metabolism in myeloid cells and T cells during Mycobacterium bovis BCG or Mtb infection, using novel genetic mouse models that allow cell-specific deletion of ACC1 and ACC2 in DCs, macrophages, or T cells. Our results demonstrate that de novo FAS is induced in DCs and macrophages upon M. bovis BCG infection. However, ACC1 expression in DCs and macrophages is not required to control mycobacteria. Similarly, absence of ACC2 did not influence the ability of DCs and macrophages to cope with infection. Furthermore, deletion of ACC1 in DCs or macrophages had no effect on systemic pro-inflammatory cytokine production or T cell priming, suggesting that FAS is dispensable for an intact innate response against mycobacteria. In contrast, mice with a deletion of ACC1 specifically in T cells fail to generate efficient T helper 1 responses and succumb early to Mtb infection. In summary, our results reveal ACC1-dependent FAS as a crucial mechanism in T cells, but not DCs or macrophages, to fight against mycobacterial infection.
2018-11-28T10:14:16Z
2018-11-28T10:14:16Z
2018-01-01
Article
1664-3224
29675017
10.3389/fimmu.2018.00495
http://hdl.handle.net/10033/621589
Attribution-NonCommercial-ShareAlike 3.0 United States
http://creativecommons.org/licenses/by-nc-sa/3.0/us/
Frontiers
Frontiers in immunology
oai:repository.helmholtz-hzi.de:10033/6216822019-08-30T11:32:39Zcom_10033_56876com_10033_6839col_10033_56896col_10033_621495
C-X-C Motif Chemokine Receptor 4 Blockade Promotes Tissue Repair After Myocardial Infarction by Enhancing Regulatory T Cell Mobilization and Immune-Regulatory Function.
Wang, Yong
Dembowsky, Klaus
Chevalier, Eric
Stüve, Philipp
Korf-Klingebiel, Mortimer
Lochner, Matthias
Napp, L Christian
Frank, Heike
Brinkmann, Eva
Kanwischer, Anna
Bauersachs, Johann
Gyongyosi, Mariann
Sparwasser, Tim
Wollert, Kai C
TWINCORE, Zentrum für experimentelle und klinische Infektionsforschung GmbH,Feodor-Lynen Str. 7, 30625 Hannover, Germany.
CXCR4 antagonist
Regulatory T cells
Acute myocardial infarction (MI) elicits an inflammatory response that drives tissue repair and adverse cardiac remodeling. Inflammatory cell trafficking after MI is controlled by C X-C motif chemokine ligand 12 (CXCL12) and its receptor, C-X-C motif chemokine receptor 4 (CXCR4). CXCR4 antagonists mobilize inflammatory cells and promote infarct repair, but the cellular mechanisms are unclear. We investigated the therapeutic potential and mode of action of the peptidic macrocycle CXCR4 antagonist POL5551 in mice with reperfused MI. We applied cell depletion and adoptive transfer strategies using lymphocyte-deficient Rag1 knockout mice; DEREG mice, which express a diphtheria toxin receptor-enhanced green fluorescent protein fusion protein under the control of the promoter/enhancer region of the regulatory T (T Intraperitoneal POL5551 injections in wild-type mice (8 mg/kg at 2, 4, 6, and 8 d) enhanced angiogenesis in the infarct border-zone, reduced scar size, and attenuated left ventricular remodeling and contractile dysfunction at 28 d. Treatment effects were absent in splenectomized wild-type mice, Rag1 knockout mice, and T Our data confirm CXCR4 blockade as a promising treatment strategy after MI. We identify dendritic cell-primed splenic T
2019-02-06T14:38:18Z
2019-02-06T14:38:18Z
2019-01-30
Article
1524-4539
30696265
10.1161/CIRCULATIONAHA.118.036053
http://hdl.handle.net/10033/621682
en
Attribution-NonCommercial-ShareAlike 4.0 International
http://creativecommons.org/licenses/by-nc-sa/4.0/
Lippinscott, Williams & Wilkins; American Heart Association
Circulation
oai:repository.helmholtz-hzi.de:10033/6231962022-06-14T01:57:16Zcom_10033_56876col_10033_56896
Characterization of Clostridioides difficile DSM 101085 with A-B-CDT+ Phenotype from a Late Recurrent Colonization.
Riedel, Thomas
Neumann-Schaal, Meina
Wittmann, Johannes
Schober, Isabel
Hofmann, Julia Danielle
Lu, Chia-Wen
Dannheim, Antonia
Zimmermann, Ortrud
Lochner, Matthias
Groß, Uwe
Overmann, Jörg
Clostridioides difficile
Clostridium difficile
R20291 resequencing
binary toxin
fermentation profile
pathogenicity locus
2022-06-13T07:40:13Z
2022-06-13T07:40:13Z
2020
2020
Article
32302381
10.1093/gbe/evaa072
http://hdl.handle.net/10033/623196
1759-6653
Genome biology and evolution
en
Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
Oxford University Press
12
5
566
577
Genome biology and evolution
England
oai:repository.helmholtz-hzi.de:10033/6232192022-06-14T01:56:32Zcom_10033_56876col_10033_56896
The Absence of HIF-1α Increases Susceptibility to Leishmania donovani Infection via Activation of BNIP3/mTOR/SREBP-1c Axis.
Mesquita, Inês
Ferreira, Carolina
Moreira, Diana
Kluck, George Eduardo Gabriel
Barbosa, Ana Margarida
Torrado, Egídio
Dinis-Oliveira, Ricardo Jorge
Gonçalves, Luís Gafeira
Beauparlant, Charles-Joly
Droit, Arnaud
Berod, Luciana
Sparwasser, Tim
Bodhale, Neelam
Saha, Bhaskar
Rodrigues, Fernando
Cunha, Cristina
Carvalho, Agostinho
Castro, António Gil
Estaquier, Jérôme
Silvestre, Ricardo
FASN
HIF-1α
SREBP-1c
acetate
lipogenesis
macrophages
myeloid cells
visceral leishmaniasis
Hypoxia-inducible factor-1 alpha (HIF-1α) is considered a global regulator of cellular metabolism and innate immune cell functions. Intracellular pathogens such as Leishmania have been reported to manipulate host cell metabolism. Herein, we demonstrate that myeloid cells from myeloid-restricted HIF-1α-deficient mice and individuals with loss-of-function HIF1A gene polymorphisms are more susceptible to L. donovani infection through increased lipogenesis. Absence of HIF-1α leads to a defect in BNIP3 expression, resulting in the activation of mTOR and nuclear translocation of SREBP-1c. We observed the induction of lipogenic gene transcripts, such as FASN, and lipid accumulation in infected HIF-1α-/- macrophages. L. donovani-infected HIF-1α-deficient mice develop hypertriglyceridemia and lipid accumulation in splenic and hepatic myeloid cells. Most importantly, our data demonstrate that manipulating FASN or SREBP-1c using pharmacological inhibitors significantly reduced parasite burden. As such, genetic deficiency of HIF-1α is associated with increased lipid accumulation, which results in impaired host-protective anti-leishmanial functions of myeloid cells.
2022-06-13T12:31:38Z
2022-06-13T12:31:38Z
2020-03-24
2019-09-02
Article
Other
32209468
10.1016/j.celrep.2020.02.098
http://hdl.handle.net/10033/623219
2211-1247
Cell reports
en
Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
Cell Press
30
12
4052
4064.e7
Cell reports
United States
United States