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

Mayer, C. T., Huntenburg, J. M., Nandan, A., Schmitt, E., Czeloth, N., & Sparwasser, T. (2013). CD4 blockade directly inhibits mouse and human CD4+ T cell functions independent of Foxp3+ Tregs. Journal of Autoimmunity, 47, 73-82. doi:10.1016/j.jaut.2013.08.008.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-002A-C171-D Version Permalink: http://hdl.handle.net/21.11116/0000-0003-856F-B
Genre: Journal Article

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 Creators:
Mayer, C. T.1, Author
Huntenburg, Julia M.1, Author              
Nandan, A.1, Author
Schmitt, E.2, Author
Czeloth, N.1, Author
Sparwasser, T.1, Author
Affiliations:
1TWINCORE Centre for Experimental and Clinical Infection Research, Hannover, Germany, ou_persistent22              
2Institute for Immunology, Johannes Gutenberg University, Mainz, Germany, ou_persistent22              

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Free keywords: Anti-CD4; YTS177.9; Foxp3; Tolerance; Autoimmunity; DEREG
 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.

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Language(s): eng - English
 Dates: 2013-08-202013-06-062013-08-262013-09-192013-12
 Publication Status: Published in print
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Method: Peer
 Identifiers: DOI: 10.1016/j.jaut.2013.08.008
BibTex Citekey: Mayer201373
PMID: 24055067
Other: Epub 2013
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Title: Journal of Autoimmunity
  Other : J. Autoimmun.
Source Genre: Journal
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Pages: - Volume / Issue: 47 Sequence Number: - Start / End Page: 73 - 82 Identifier: ISSN: 0896-8411
CoNE: https://pure.mpg.de/cone/journals/resource/954922649139