IL-6 controls Th17 immunity in vivo by inhibiting the conversion of conventional T cells into Foxp3+ regulatory T cells

Thomas Korn, Meike Mitsdoerffer, Andrew L. Croxford, Amit Awasthi, Valérie A. Dardalhon, George Galileos, Patrick Vollmar, Gretta L. Stritesky, Mark H. Kaplan, Ari Waisman, Vijay K. Kuchroo, Mohamed Oukka

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329 Scopus citations

Abstract

The conditions leading to the induction of adaptive Foxp3+ regulatory T cells (T-regs) from peripheral T cells in vivo are incompletely understood. Here, we show that unresponsiveness of T cells to IL-6 by T cell-selective deletion of gp130 or immunization of wild-type mice with antigen in incomplete Freund's adjuvant (IFA), which fails to induce IL-6, promotes the conversion of peripheral CD4+ T cells into adaptive Foxp3+ T-regs. Thus, both T cell-conditional gp130 knockout (KO) mice immunized with MOG35-55 in complete Freund's adjuvant (CFA) and wild-type mice immunized with MOG35-55 in IFA develop overwhelming antigen-specific T-reg responses and are protected from experimental autoimmune encephalomyelitis (EAE). Depletion of T-regs restores T helper (Th)17 responses and clinical EAE in MOG/CFA-immunized T cell-conditional gp130 KO mice, but not in MOG/IFA-immunized wild-type mice. We conclude that in the absence of T-regs, IL-6 signaling is dispensable for the induction of Th17 cells, and alternative pathways exist to induce Th17 cells and EAE in the absence of IL-6 signaling. However, IL-6 signaling is dominant in inhibiting the conversion of conventional T cells into Foxp3+ T-regs in vivo, and in the absence of IL-6 signaling, no other cytokine can substitute in inhibiting T-reg conversion. These data identify IL-6 as an important target to modulate autoimmune responses and chronic inflammation.

Original languageEnglish (US)
Pages (from-to)18460-18465
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume105
Issue number47
DOIs
StatePublished - Nov 25 2008

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Keywords

  • Experimental autoimmune encephalomyelitis
  • IL-21
  • Incomplete Freund's adjuvant
  • Multiple sclerosis
  • Tolerance

ASJC Scopus subject areas

  • General

Cite this

Korn, T., Mitsdoerffer, M., Croxford, A. L., Awasthi, A., Dardalhon, V. A., Galileos, G., Vollmar, P., Stritesky, G. L., Kaplan, M. H., Waisman, A., Kuchroo, V. K., & Oukka, M. (2008). IL-6 controls Th17 immunity in vivo by inhibiting the conversion of conventional T cells into Foxp3+ regulatory T cells. Proceedings of the National Academy of Sciences of the United States of America, 105(47), 18460-18465. https://doi.org/10.1073/pnas.0809850105