Analysis of T cell Tolerance induction against the retinal self- antigen IRBP

光受体间类视黄醇结合蛋白(IRBP)定位于视网膜和松果体，具有高度的免疫致病性，能够在多种动物中诱导实验性自身免疫性葡萄膜视网膜炎。然而，由于IRBP等自身抗原通常存在于体内而不会引起葡萄膜视网膜炎，因此通常情况下自我耐受性的形成仍然知之甚少。然而，最近的工作提供了直接证据表明，T细胞耐受可以通过至少两种不同的机制发生，包括与自身抗原的相互作用：胸腺的克隆性删除和外周的无能。在这项研究中，我们研究了内源性IRBP是否也影响T细胞对它的耐受的诱导。为此，我们摘除了裸鼠的眼睛和松果体以消除内源性IRBP，并通过胚胎同种异体小鼠胸腺移植(OxPxTg裸鼠)重建了它们的T细胞功能。然后，当我们检测IRBP刺激的OxPxTg小鼠的淋巴细胞反应时，我们观察到了显著的增殖反应和IL-2的产生，而正常BALB/c小鼠则没有。此外，从OxPxTg裸鼠体内建立的IRBP特异性T细胞株能够诱导完整的BALB/c裸鼠发生葡萄膜视网膜炎。由于这些发现，我们阐明了器官特异性自身抗原IRBP不仅是被称为葡萄膜视网膜炎的自身免疫性疾病的靶抗原，而且在正常状态下，它也参与了T细胞对自身的耐受(IRBP)的获得。

Interphotoreceptor retinoid-binding protein (IRBP), which localizes specifically in the retina and the pineal gland, has been found to be highly immunopathogenic and capable of inducing experimental autoimmune uveoretinitis in a variety of animal species. However, since self-antigens such as IRBP normally exist in the body without causing uveoretinitis, it follows that self tolerance usually develops is still poorly understood. Nevertheless, recent work has provided direct evidence that T cell tolerance can occur by at least two different mechanisms involving interaction with self-antigens : clonal deletion in the thymus, and anergy in the periphery. In this study, we investigated whether endogenous IRBP also influences the induction of T cell tolerance against it. To that end, we removed the eyes and pineal glands of nude mice to eliminate endogenous IRBP,and reconstituted their T cell function by embryonic syngenic mouse thymus grafting (OxPxTg nude mice). Then, when we examined the lymphocyte response of the OxPxTg mice stimulated with IRBP,the significant proliferative response and production of IL-2 were observed, but not to be shown in that of normal BALB/c mice. Moreover, an IRBP specific T cell line established from the OxPxTg nude mice transferred into intact BALB/c nude mice was capable of inducing uveoretinitis. As a result of these findings, we elucidated that the organ-specific self-antigen IRBP is not merely the target antigen of the autoimmune disease known as uveoretinitis, but in the normal state it is also involved in the acquisition of T cell tolerance to itself (IRBP).