Sugita Sunao, Horie Shintaro, Nakamura Orie, Maruyama Kazuichi, Takase Hiroshi, Usui Yoshihiko, Takeuchi Masaru, Ishidoh Kazumi, Koike Masato, Uchiyama Yasuo, Peters Christoph, Yamamoto Yoshimi, Mochizuki Manabu
Department of Ophthalmology and Visual Science, Tokyo Medical and Dental University Graduate School of Medicine and Dental Sciences, Tokyo, Japan.
J Immunol. 2009 Oct 15;183(8):5013-22. doi: 10.4049/jimmunol.0901623.
Pigment epithelium isolated from the eye possesses immunosuppressive properties such as regulatory T (Treg) cell induction; e.g., cultured retinal pigment epithelium (RPE) converts CD4(+) T cells into Treg cells in vitro. RPE constitutively expresses a novel immunosuppressive factor, CTLA-2alpha, which is a cathepsin L (CathL) inhibitor, and this molecule acts via RPE to induce Treg cells. To clarify CTLA-2alpha's role in the T cell response to RPE in ocular inflammation, we used the experimental autoimmune uveitis (EAU) animal model to examine this new immunosuppressive property of RPE. In EAU models, TGF-beta, but not IFN-gamma inflammatory cytokines, promotes the up-regulation of the expression of CTLA-2alpha in RPE. Similarly, CTLA-2alpha via RPE was able to promote TGF-beta production by the CD4(+) T cells. The RPE-exposed T cells (RPE-induced Treg cells) greatly produced TGF-beta and suppressed bystander effector T cells. There was less expression of CathL by the RPE-exposed T cells, and CathL-inhibited T cells were able to acquire the Treg phenotype. Moreover, CathL-deficient mice spontaneously produced Treg cells, with the increase in T cells potentially providing protection against ocular inflammation. More importantly, CD4(+) T cells from EAU in CathL knockout mice or rCTLA-2alpha from EAU animals were found to contain a high population of forkhead box p3(+) T cells. In both EAU models, there was significant suppression of the ocular inflammation. These results indicate that RPE secretes CTLA-2alpha, thereby enabling the bystander T cells to be converted into Treg cells via TGF-beta promotion.
从眼中分离出的色素上皮具有免疫抑制特性，如诱导调节性T（Treg）细胞；例如，培养的视网膜色素上皮（RPE）在体外可将CD4(+) T细胞转化为Treg细胞。RPE组成性表达一种新型免疫抑制因子CTLA-2α，它是组织蛋白酶L（CathL）的抑制剂，该分子通过RPE发挥作用来诱导Treg细胞。为了阐明CTLA-2α在眼部炎症中T细胞对RPE反应中的作用，我们使用实验性自身免疫性葡萄膜炎（EAU）动物模型来研究RPE的这种新的免疫抑制特性。在EAU模型中，转化生长因子-β（TGF-β）而非干扰素-γ（IFN-γ）炎性细胞因子可促进RPE中CTLA-2α表达的上调。同样，通过RPE的CTLA-2α能够促进CD4(+) T细胞产生TGF-β。暴露于RPE的T细胞（RPE诱导的Treg细胞）大量产生TGF-β并抑制旁观者效应T细胞。暴露于RPE的T细胞中CathL的表达较少，并且CathL抑制的T细胞能够获得Treg表型。此外，CathL缺陷小鼠自发产生Treg细胞，T细胞的增加可能为眼部炎症提供保护。更重要的是，发现来自CathL基因敲除小鼠的EAU中的CD4(+) T细胞或来自EAU动物的重组CTLA-2α含有大量叉头框p3(+) T细胞。在两个EAU模型中，眼部炎症均得到显著抑制。这些结果表明，RPE分泌CTLA-2α，从而使旁观者T细胞能够通过TGF-β的促进作用转化为Treg细胞。
