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

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 105; no. 47; pp. 18460 - 18465
• Main Authors: Korn, Thomas, Mitsdoerffer, Meike, Croxford, Andrew L, Awasthi, Amit, Dardalhon, Valérie A, Galileos, George, Vollmar, Patrick, Stritesky, Gretta L, Kaplan, Mark H, Waisman, Ari, Kuchroo, Vijay K, Oukka, Mohamed
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 25.11.2008; National Acad Sciences
• Subjects: Animals; Antigen presenting cells; Antigens; Biological Sciences; Cytokines; Drug regulation; Encephalomyelitis, Autoimmune, Experimental - immunology; Encephalomyelitis, Autoimmune, Experimental - prevention & control; Forkhead Transcription Factors - immunology; Freunds adjuvant; Immune tolerance; Immunization; Interleukin-6 - biosynthesis; Interleukin-6 - physiology; Mice; Mice, Knockout; Rodents; Splenocytes; T cell receptors; T lymphocytes; T-Lymphocytes, Helper-Inducer - immunology; T-Lymphocytes, Regulatory - immunology
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0809850105

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.