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

• DOI: 10.1073/pnas.0809850105
• Publication Date: 2008-11-18T02:40:39Z
• Authors: 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
• Keywords: Mice, Knockout; Mice; 03 medical and health sciences; Encephalomyelitis, Autoimmune, Experimental; 0302 clinical medicine; Interleukin-6; Animals; Forkhead Transcription Factors; T-Lymphocytes, Helper-Inducer; T-Lymphocytes, Regulatory; 3. Good health

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.