期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 105, 期 47, 页码 18460-18465出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0809850105
关键词
experimental autoimmune encephalomyelitis; multiple sclerosis; IL-21; tolerance; incomplete Freund's adjuvant
资金
- National Institutes of Health [R01AI073542-01, 1ROlNS045937-01, 2ROINS35685-06-, 2R37NS30843-11, 1R01A144880-03, 2P01A139671-07, 1POlNS38037-04, 1R01NS046414]
- National Multiple Sclerosis Society [RG-2571-D-9, RG-3882-A-1]
- Juvenile Diabetes Research Foundation
- Center for Immunological Tolerance
- Harvard Medical School
- Deutsche Forschungsgemeinschaft [2964/2-1, 1221/1-1, SFB490, SFBfTR52]
- FP6 Marie Curie Research Training Network [MRTN-CT-2004-005632]
- IMDEMI
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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