Tregs restrain dendritic cell autophagy to ameliorate autoimmunity.

2.50
Hdl Handle:
http://hdl.handle.net/10033/621035
Title:
Tregs restrain dendritic cell autophagy to ameliorate autoimmunity.
Authors:
Alissafi, Themis; Banos, Aggelos; Boon, Louis; Sparwasser, Tim ( 0000-0001-5645-902X ) ; Ghigo, Alessandra; Wing, Kajsa; Vassilopoulos, Dimitrios; Boumpas, Dimitrios; Chavakis, Triantafyllos; Cadwell, Ken; Verginis, Panayotis
Abstract:
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.
Affiliation:
TWINCORE, Zentrum für experimentelle und klinische Infektionsforschung GmbH, Feodor-Lynnen Str. 7,30625 Hannover, Germany.
Citation:
Tregs restrain dendritic cell autophagy to ameliorate autoimmunity. 2017, 127 (7):2789-2804 J. Clin. Invest.
Journal:
The Journal of clinical investigation
Issue Date:
30-Jun-2017
URI:
http://hdl.handle.net/10033/621035
DOI:
10.1172/JCI92079
PubMed ID:
28581446
Type:
Article
Language:
en
ISSN:
1558-8238
Appears in Collections:
publications of the TwinCore unit Infection immunology

Full metadata record

DC FieldValue Language
dc.contributor.authorAlissafi, Themisen
dc.contributor.authorBanos, Aggelosen
dc.contributor.authorBoon, Louisen
dc.contributor.authorSparwasser, Timen
dc.contributor.authorGhigo, Alessandraen
dc.contributor.authorWing, Kajsaen
dc.contributor.authorVassilopoulos, Dimitriosen
dc.contributor.authorBoumpas, Dimitriosen
dc.contributor.authorChavakis, Triantafyllosen
dc.contributor.authorCadwell, Kenen
dc.contributor.authorVerginis, Panayotisen
dc.date.accessioned2017-08-02T13:32:42Z-
dc.date.available2017-08-02T13:32:42Z-
dc.date.issued2017-06-30-
dc.identifier.citationTregs restrain dendritic cell autophagy to ameliorate autoimmunity. 2017, 127 (7):2789-2804 J. Clin. Invest.en
dc.identifier.issn1558-8238-
dc.identifier.pmid28581446-
dc.identifier.doi10.1172/JCI92079-
dc.identifier.urihttp://hdl.handle.net/10033/621035-
dc.description.abstractDesign 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.en
dc.language.isoenen
dc.rights.urihttp://creativecommons.org/licenses/by-nc-sa/4.0/*
dc.titleTregs restrain dendritic cell autophagy to ameliorate autoimmunity.en
dc.typeArticleen
dc.contributor.departmentTWINCORE, Zentrum für experimentelle und klinische Infektionsforschung GmbH, Feodor-Lynnen Str. 7,30625 Hannover, Germany.en
dc.identifier.journalThe Journal of clinical investigationen

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