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 Kaplan, Ari Waisman, Vijay K. Kuchroo, Mohamed Oukka

Research output: Contribution to journalArticle

323 Citations (Scopus)

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
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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Regulatory T-Lymphocytes
Immunity
Interleukin-6
T-Lymphocytes
Autoimmune Experimental Encephalomyelitis
Th17 Cells
Freund's Adjuvant
Knockout Mice
Viral Tumor Antigens
Autoimmunity
Immunization
Cytokines
Inflammation
Antigens
incomplete Freund's adjuvant

Keywords

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

ASJC Scopus subject areas

  • General

Cite this

IL-6 controls Th17 immunity in vivo by inhibiting the conversion of conventional T cells into Foxp3+ regulatory T cells. / Korn, Thomas; Mitsdoerffer, Meike; Croxford, Andrew L.; Awasthi, Amit; Dardalhon, Valérie A.; Galileos, George; Vollmar, Patrick; Stritesky, Gretta L.; Kaplan, Mark; Waisman, Ari; Kuchroo, Vijay K.; Oukka, Mohamed.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 105, No. 47, 25.11.2008, p. 18460-18465.

Research output: Contribution to journalArticle

Korn, T, Mitsdoerffer, M, Croxford, AL, Awasthi, A, Dardalhon, VA, Galileos, G, Vollmar, P, Stritesky, GL, Kaplan, M, Waisman, A, Kuchroo, VK & 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, vol. 105, no. 47, pp. 18460-18465. https://doi.org/10.1073/pnas.0809850105
Korn, Thomas ; Mitsdoerffer, Meike ; Croxford, Andrew L. ; Awasthi, Amit ; Dardalhon, Valérie A. ; Galileos, George ; Vollmar, Patrick ; Stritesky, Gretta L. ; Kaplan, Mark ; Waisman, Ari ; Kuchroo, Vijay K. ; Oukka, Mohamed. / IL-6 controls Th17 immunity in vivo by inhibiting the conversion of conventional T cells into Foxp3+ regulatory T cells. In: Proceedings of the National Academy of Sciences of the United States of America. 2008 ; Vol. 105, No. 47. pp. 18460-18465.
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AU - Awasthi, Amit

AU - Dardalhon, Valérie A.

AU - Galileos, George

AU - Vollmar, Patrick

AU - Stritesky, Gretta L.

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AB - 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.

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