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J Clin Invest. 2008 May;118(5):1680-90. doi: 10.1172/JCI33342.

The type I IFN induction pathway constrains Th17-mediated autoimmune inflammation in mice.

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  • 1Department of Microbiology, Immunology, and Molecular Genetics, 8-240 Factor Building, University of California, 10833 Le Conte Avenue, Los Angeles, California 90095, USA.

Abstract

IFN-beta, a type I IFN, is widely used for the treatment of MS. However, the mechanisms behind its therapeutic efficacy are not well understood. Using a murine model of MS, EAE, we demonstrate that the Th17-mediated development of autoimmune disease is constrained by Toll-IL-1 receptor domain-containing adaptor inducing IFN-beta-dependent (TRIF-dependent) type I IFN production and its downstream signaling pathway. Mice with defects in TRIF or type I IFN receptor (IFNAR) developed more severe EAE. Notably, these mice exhibited marked CNS inflammation, as manifested by increased IL-17 production. In addition, IFNAR-dependent signaling events were essential for negatively regulating Th17 development. Finally, IFN-beta-mediated IL-27 production by innate immune cells was critical for the immunoregulatory role of IFN-beta in the CNS autoimmune disease. Together, our findings not only may provide a molecular mechanism for the clinical benefits of IFN-beta in MS but also demonstrate a regulatory role for type I IFN induction and its downstream signaling pathways in limiting Th17 development and autoimmune inflammation.

PMID:
18382764
[PubMed - indexed for MEDLINE]
PMCID:
PMC2276397
Free PMC Article
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