Departments of Ophthalmology, Tokyo Medical University, Tokyo, Japan.
Invest Ophthalmol Vis Sci. 2010 Apr;51(4):2109-17. doi: 10.1167/iovs.09-3993. Epub 2009 Dec 10.
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.
目的。芳香烃受体（AHR）已被鉴定为调节 CD25(+)CD4(+)调节性 T 细胞（T(reg)）和 Th17 细胞分化的调节剂，其配体 2,3,7,8-四氯二苯并-p-二恶英（TCDD）激活 AHR 可诱导功能性 T(reg)细胞。在这项研究中，作者研究了 TCDD 是否通过诱导 T(reg)细胞分化来抑制小鼠实验性自身免疫性葡萄膜炎（EAU）。
方法。在免疫人眼间维生素 A 结合蛋白肽 1-20（hIRBP-p）之前，用 TCDD 对 C57BL/6 小鼠进行注射，然后通过临床和组织病理学评估 EAU 的严重程度。通过 T 细胞增殖和细胞因子产生评估引流淋巴结细胞和脾细胞对 hIRBP-p 和抗 CD3 单克隆抗体（mAb）的免疫反应。此外，还评估了 Foxp3(+)T 细胞的分化及其在 TCDD 注射小鼠中的免疫抑制作用。
结果。TCDD 注射增加了淋巴结和脾脏中的 Foxp3(+)T 细胞。TCDD 注射完全抑制了 EAU 的发展，而在 TCDD 注射前用抗 CD25 mAb 处理则消除了抑制作用。用 hIRBP-p 免疫的 TCDD 注射小鼠的淋巴细胞和脾细胞在刺激 hIRBP-p 时均不能产生 IFN-γ和 IL-17，即使在刺激抗 CD3 mAb 时也观察到 IL-17 产生的失败。然而，当用抗 CD3 mAb 刺激时，该方案不干扰 IL-10 产生和 T 细胞增殖反应。
结论。TCDD 通过扩展 CD25(+)Foxp3(+)T(reg)细胞并干扰 Th1 和 Th17 细胞的激活来显著抑制自身免疫性葡萄膜炎。
