Suppression of experimental autoimmune uveoretinitis by inducing differentiation of regulatory T cells via activation of aryl hydrocarbon receptor.

Purpose. Aryl hydrocarbon receptor (AHR) has been identified as a regulator of CD25(+)CD4(+) regulatory T-cell (T(reg)) and Th17 cell differentiation in mice, and activation of AHR by its ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induces functional T(reg) cells. In this study, the authors examined whether the AHR-mediated effect of TCDD suppresses mouse experimental autoimmune uveitis (EAU) by inducing T(reg) cell differentiation. Methods. C57BL/6 mice were injected with TCDD 1 day before immunization with human interphotoreceptor retinoid-binding protein peptide 1-20 (hIRBP-p), and the severity of EAU was assessed clinically and histopathologically. Immunologic responses of draining lymph node cells and splenocytes to hIRBP-p and anti-CD3 monoclonal antibody (mAb) were assessed by T-cell proliferation and cytokine production. In addition, differentiation of Foxp3(+) T cells and their immunosuppressive roles in TCDD-injected mice were evaluated. Results. TCDD injection increased Foxp3(+) T cells in the lymph nodes and in the spleen. Development of EAU was completely suppressed by TCDD injection, and suppression was abolished by treatment with anti-CD25 mAb before TCDD injection. Both lymphocytes and splenocytes obtained from TCDD-injected mice immunized with hIRBP-p failed to produce IFN-gamma and IL-17 on stimulation with hIRBP-p, and the failure of IL-17 production was observed even when stimulated with anti-CD3 mAb. However, this protocol did not interfere with IL-10 production and T-cell proliferation response when assessed on stimulation with anti-CD3 mAb. Conclusions. Activation of AHR by TCDD markedly suppressed autoimmune uveoretinitis through mechanisms that expand CD25(+)Foxp3(+) T(reg) cells and interfere with the activation of Th1 and Th17 cells.