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R.S. Grajewski, P.B. Silver, R.K. Agarwal, S.B. Su, C.C. Chan, G.I. Liou, R.R. Caspi; Endogenous Expression of IRBP Is Not Required for Generation of CD4+CD25+ Regulatory T Cells That Protect Against IRBP–Induced Experimental Autoimmune Uveitis (EAU) . Invest. Ophthalmol. Vis. Sci. 2005;46(13):1134.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: "Natural" CD4+CD25+ regulatory T cells (T–reg) develop in the thymus, apparently as a result of interaction with their cognate antigen. We previously showed that susceptibility to EAU induced with the retinal autoantigen IRBP is controlled by thymus–derived T–reg. In this study we examine whether endogenous expression of IRBP is necessary to generate EAU–relevant T–reg, by comparing generation of uveitogenic T cells and immunological responses to IRBP in IRBP knockout (KO) and wild type (WT) mice. We hypothesized that, if endogenous IRBP is needed to generate EAU–relevant T–regs, depletion of CD25+ cells from IRBP KO mice will fail to enhance these responses. Methods:CD25+ cells were depleted by treatment with the monoclonal antibody PC61. Mice were immunized with IRBP in complete (CFA) or incomplete (IFA) Freund’s adjuvant, or were given T cells from IRBP–immunized donors. EAU scores and associated immunological responses (delayed hypersensitivity and proliferation to IRBP) were examined. Results:Both WT and KO mice depleted of CD25+ cells and immunized with IRBP in CFA had enhanced immune responses to IRBP. Furthermore, IRBP primed T cells of CD25 depleted KO donors elicited more severe disease in WT recipients than did cells from nondepleted KO donors, suggesting that an EAU–relevant T–reg had been removed. In contrast, when immunized with IRBP/IFA only the depleted WT, but not the depleted KO mice, had enhanced IRBP–specific immune responses, suggesting that IRBP specific T–regs were present only in WT. Conclusions:Our results suggest that although endogenous expression of IRBP is needed to generate IRBP–specific T–regs, EAU–relevant T–regs are present in IRBP KO mice. We propose that these are T–regs activated by microbial components present in CFA, that, once activated, inhibit development of IRBP–specific effector T cells in an antigen–nonspecific manner. Thus, EAU and responses to IRBP may be inhibited by T–regs activated by innate and/or microbial stimuli.
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