CD4 blockade directly inhibits mouse and human CD4(+) T cell functions independent of Foxp3(+) Tregs.

2.50
Hdl Handle:
http://hdl.handle.net/10033/317818
Title:
CD4 blockade directly inhibits mouse and human CD4(+) T cell functions independent of Foxp3(+) Tregs.
Authors:
Mayer, C T; Huntenburg, J; Nandan, A; Schmitt, E; Czeloth, N; Sparwasser, T ( 0000-0001-5645-902X )
Abstract:
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.
Citation:
CD4 blockade directly inhibits mouse and human CD4(+) T cell functions independent of Foxp3(+) Tregs. 2013, 47:73-82 J. Autoimmun.
Publisher:
Elsevier Science
Journal:
Journal of autoimmunity
Issue Date:
Dec-2013
URI:
http://hdl.handle.net/10033/317818
DOI:
10.1016/j.jaut.2013.08.008
PubMed ID:
24055067
Type:
Article
Language:
en
ISSN:
1095-9157
Appears in Collections:
publications of the TwinCore unit Infection immunology

Full metadata record

DC FieldValue Language
dc.contributor.authorMayer, C Ten
dc.contributor.authorHuntenburg, Jen
dc.contributor.authorNandan, Aen
dc.contributor.authorSchmitt, Een
dc.contributor.authorCzeloth, Nen
dc.contributor.authorSparwasser, Ten
dc.date.accessioned2014-06-03T14:29:57Zen
dc.date.available2014-06-03T14:29:57Zen
dc.date.issued2013-12en
dc.identifier.citationCD4 blockade directly inhibits mouse and human CD4(+) T cell functions independent of Foxp3(+) Tregs. 2013, 47:73-82 J. Autoimmun.en
dc.identifier.issn1095-9157en
dc.identifier.pmid24055067en
dc.identifier.doi10.1016/j.jaut.2013.08.008en
dc.identifier.urihttp://hdl.handle.net/10033/317818en
dc.description.abstractCD4(+) 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.en
dc.language.isoenen
dc.publisherElsevier Scienceen
dc.rightsArchived with thanks to Journal of autoimmunityen
dc.titleCD4 blockade directly inhibits mouse and human CD4(+) T cell functions independent of Foxp3(+) Tregs.en
dc.typeArticleen
dc.identifier.journalJournal of autoimmunityen

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