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Section of Molecular Immunology, Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, MD 20892
Th17 cells are implicated in CNS autoimmune diseases. We show that mice with targeted-deletion of Stat3 in CD4+ T cells (CD4Stat3–/–) do not develop experimental autoimmune uveoretinitis (EAU) or experimental autoimmune encephalomyelitis. Defective Th17 differentiation noted in CD4Stat3–/– mice is compensated by exaggerated increases in Foxp3-, IL-10-, IL-4-, and IFN-
-expressing T cells, suggesting critical roles of STAT3 in shaping Ag-specific CD4+ T cell repertoire. In mice with EAU, a high percentage of IL-17-expressing T cells in their peripheral lymphoid organs also secrete IFN- while these double-expressors are absent in CD4Stat3–/– and wild-type mice without EAU, raising the intriguing possibility that uveitis maybe mediated by Th17 and IL-17-expressing Th1 cells. Resistance of Stat3-deficient mice to EAU derives in part from an inability of uveitogenic Th17 and Th1 cells to enter eyes or brain of the CD4Stat3–/– mouse because of the reduction in the expression of activated 
4/β1 integrins on CD4Stat3–/– T cells. Adoptive transfer of activated interphotoreceptor retinoid-binding protein-specific uveitogenic T cells induced in CD4Stat3–/– mice a severe EAU characterized by development of retinal folds, infiltration of inflammatory cells into the retina, and destruction of retinal architecture, underscoring our contention that the loss of STAT3 in CD4+ T cells results in an intrinsic developmental defect that renders CD4Stat3–/– resistant to CNS inflammatory diseases. STAT3 requirement for IL-17 production by Th17, generation of double positive T cells expressing IL-17 and IFN-, and for T cell trafficking into CNS tissues suggests that STAT3 may be a therapeutic target for modulating uveitis, sceritis, or multiple sclerosis.
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 Address correspondence and reprint requests to Dr. Charles E. Egwuagu, Molecular Immunology Section, Laboratory of Immunology, National Institutes of Health, Building 10, Room 10N116, 10 Center Drive, Bethesda, MD 20892. E-mail address: egwuaguc{at}nei.nih.gov
2 Abbreviations used in this paper: EAU, experimental autoimmune uveoretinitis; Treg, T regulatory cell; EAE, experimental autoimmune encephalomyelitis; IRBP, interphotoreceptor retinoid-binding protein; WT, wild type; MOG, myelin oligodendrocyte glycoprotein; PPD, purified protein derivative; DP, double positive.
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