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* Department of Neurology; and
Center for Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390
IL-17-producing T cells (Th17) have recently been implicated in the pathogenesis of experimental autoimmune encephalomyelitis (EAE), an animal model for the human disease multiple sclerosis. However, little is known about the transcription factors that regulate these cells. Although it is clear that the transcription factor T-bet plays an essential role in the differentiation of IFN-
-producing CD4+ Th1 lymphocytes, the potential role of T-bet in the differentiation of Th17 cells is not completely understood. In this study, therapeutic administration of a small interfering RNA specific for T-bet significantly improved the clinical course of established EAE. The improved clinical course was associated with suppression of newly differentiated T cells that express IL-17 in the CNS as well as suppression of myelin basic protein-specific Th1 autoreactive T cells. Moreover, T-bet was found to directly regulate transcription of the IL-23R, and, in doing so, influenced the fate of Th17 cells, which depend on optimal IL-23 production for survival. We now show for the first time that suppression of T-bet ameliorates EAE by limiting the differentiation of autoreactive Th1 cells, as well as inhibiting pathogenic Th17 cells via regulation of IL-23R.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 These studies were supported, in part, by U.S. Public Health Service National Institutes of Health Grants NS37513 and NS44250 and National Multiple Sclerosis Society Grant RG2969-B-7 (to M.K.R.). A.E.L.-R. is a National Multiple Sclerosis Society Harry Weaver Neuroscience Scholar.
2 Address correspondence and reprint requests to Michael K. Racke, Department of Neurology, Ohio State University Medical Center, 1654 Upham Drive, 445 Means Hall, Columbus, OH 43210. E-mail address: Michael.Racke{at}osumc.edu
3 Abbreviations used in this paper: EAE, experimental autoimmune encephalomyelitis; MS, multiple sclerosis; siRNA, small interfering RNA; MBP, myelin basic protein; siRNA-NS, non-sense siRNA; siRNA-T-bet, T-bet-specific siRNA; ChIP, chromatin immunoprecipitation; EAM, experimental autoimmune myocarditis.
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