Abrogation of Rbpj attenuates experimental autoimmune uveoretinitis by inhibiting IL-22-producing CD4+ T cells.
Abrogation of Rbpj attenuates experimental autoimmune uveoretinitis by inhibiting IL-22-producing CD4+ T cells.
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DOI：
10.1371/journal.pone.0089266
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Yasutomo K
中科院分区：
文献类型：
--
作者：
Bhuyan ZA;Asanoma M;Iwata A;Ishifune C;Maekawa Y;Shimada M;Yasutomo K
实验性自身免疫性葡萄膜视网膜炎(EAU)是用光感受器间视黄酸结合蛋白(IRBP)免疫小鼠而引起的一种器官特异性T细胞介导的疾病。自身侵袭性CD4+T细胞是EAU的主要致病细胞群。我们研究了T细胞中的Notch信号在EAU发病机制中的作用，因为Notch信号调节着CD4+T细胞功能的各个方面。Rbpj是Notch信号转导所必需的，T细胞中Rbpj缺乏抑制了EAU疾病的严重程度。T细胞特异性Rbpj缺陷小鼠EAU的改善与CD4+T细胞产生IL-22的低水平有关，尽管IRBP特异性CD4+T细胞的增殖和Th17分化没有受到影响。在EAU的晚期而不是早期阶段应用重组IL-22可提高T细胞特异性Rbpj缺陷小鼠的EAU临床评分。用γ分泌酶抑制剂(GSI)免疫IRBP的小鼠，即使在免疫后13天才给予GSI，也能抑制EAU的进展。我们的数据表明Rbpj/Notch介导的T细胞产生IL-22在EAU的晚期具有重要的病理作用，并提示Notch阻断可能是治疗EAU的一种有效的治疗方法。
Experimental autoimmune uveoretinitis (EAU) is an organ-specific T cell-mediated disease induced by immunizing mice with interphotoreceptor retinoid binding protein (IRBP). Autoaggressive CD4+ T cells are the major pathogenic population for EAU. We investigated the contribution of Notch signaling in T cells to EAU pathogenesis because Notch signaling regulates various aspects of CD4+ T cell functions. Rbpj is required for Notch signaling, and Rbpj deficiency in T cells inhibited EAU disease severity. The amelioration of EAU in T cell-specific Rbpj-deficient mice correlated with low levels of IL-22 production from CD4+ T cells, although IRBP-specific CD4+ T cell proliferation and Th17 differentiation were unaffected. Administration of recombinant IL-22 during the late phase, but not the early phase, of EAU increased EAU clinical scores in T cell-specific Rbpj-deficient mice. Notch inhibition in mice immunized with IRBP with a γ-secretase inhibitor (GSI) suppressed EAU progression, even when GSI was administered as late as 13 days after IRBP immunization. Our data demonstrate that Rbpj/Notch-mediated IL-22 production in T cells has a key pathological role in the late phase of EAU, and suggest that Notch blockade might be a useful therapeutic approach for treating EAU.
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DOI：
10.1084/jem.189.2.219
发表时间：
1999-01-18
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Tarrant TK;Silver PB;Wahlsten JL;Rizzo LV;Chan CC;Wiggert B;Caspi RR
通讯作者：
Caspi RR
影响因子：
4.4
作者：
Caspi, RR
通讯作者：
Caspi, RR
影响因子：
32.4
作者：
Tanigaki, K;Tsuji, M;Honjo, T
通讯作者：
Honjo, T
影响因子：
4.4
作者：
Kitamura, Mizuki;Iwabuchi, Kazuya;Onoe, Kazunori
通讯作者：
Onoe, Kazunori
影响因子：
4.4
作者：
Sonoda, KH;Sasa, Y;Ishibashi, T
通讯作者：
Ishibashi, T