Local Generation of Regulatory T Cells to Retinal Antigen

描述（由申请人提供）：几项研究表明免疫系统维持调节和效应活性的稳态平衡。由于IL-2、CD25、FoxP3或aire缺乏或新生儿胸腺切除术导致调节性T细胞活性的丧失或抑制，可能导致T细胞介导的广泛的灾难性自身免疫，其靶标包括眼睛组织。许多组织特异性抗原在胸腺中享受异位表达，部分原因是由于aire活性，提供了产生多种调节性T细胞的机会，以产生自身抗原，并保护自身免疫。这些自然调节性T细胞（nTregs）是宿主生存所必需的。在TGF和视黄酸等促进Treg分化的条件下，成熟T细胞（iTregs）在遇到自身和外来抗原时也会在外周诱导Treg。在许多情况下，这些产生treg的相互作用发生在淋巴组织，包括淋巴结。也有证据表明，一些组织中存在明显的“常驻”treg；这些组织包括皮肤、脂肪组织和胃肠道，它们的局部活动似乎有助于组织稳态。我们的初步研究表明，局部生成的treg可能是在视网膜抗原反应过程中发现的，这一过程我们称之为“按需”treg。我们在正常视网膜的薄壁组织中发现了一小群T细胞。这些T细胞的一个子集使用foxp3启动子表达Tregs的转基因标记。我们认为这些Treg细胞是局部产生的，并且是视网膜免疫稳态维持的持续贡献的证据。我们进一步提出，它们是由具有调节性抗原呈递细胞活性的局部视网膜树突状细胞诱导和维持的。这些假设将在以下目标中进行探讨。目的1询问Tregs在正常的、静止的视网膜中的存在是否通过它们对视网膜抗原特异性的T细胞受体的表达而促进。

DESCRIPTION (provided by applicant): Several lines of research demonstrate that the immune system maintains a homeostatic balance of regulatory and effector activity. Loss or inhibition of the activity of regulatory T cells, by deficiency in IL-2, CD25, FoxP3, or aire, or b neonatal thymectomy, may result in widespread catastrophic autoimmunity mediated by T cells whose targets include tissues of the eye. Many tissue-specific antigens enjoy ectopic expression in the thymus, in part due to aire activity, providing the opportunity to generate a diverse repertoire of regulatory T cells to self-antigens, and protection from autoimmunity. These natural regulatory T cells (nTregs) are required for survival of the host. Tregs are also induced in the periphery from mature T cells (iTregs) upon encounter with antigens, both self and foreign, under conditions that promote Treg differentiation, including the presence of TGF and retinoic acid. In many cases these Treg-generating interactions take place in lymphoid tissues, including lymph nodes. There is also evidence that some tissues are populated by apparently "resident" Tregs; these tissues include skin, adipose tissue, and the gastro-intestinal tract where their local activity appears to contribute to tissue homeostasis. Our preliminary studies suggest that local generation of Tregs may be found during responses to retinal antigens, a process we refer to as "on-demand" Tregs. We have found a small population of T cells in the parenchyma of the normal retina. A subset of these T cells expresses a transgenic marker for Tregs using the foxp3 promoter. We propose that these Treg cells are generated locally, and are evidence of an on-going contribution to maintenance of immune homeostasis in the retina. We further propose that they are induced and maintained by the presence of local retinal dendritic cells with regulatory antigen presenting cell activity. These hypotheses are explored in the following Aims. Aim 1 asks if the presence of Tregs in the normal, quiescent retina is promoted by their expression of a T cell receptor with specificity for a retinal antigen. Aim 2 examines the hypothesis that the function of retinal Tregs is to protect the retina from EAU or other local inflammation and examines their phenotype before and after local injury or retinal inflammation. Aim 3 will test their origin, and examine our hypothesis that they are made "on-demand". PUBLIC HEALTH RELEVANCE: Inflammatory diseases of the eye pose a serious threat of blindness or visual impairment if they affect the tissues of the visual axis. The eye, and retina, have developed strategies to maintain essential immune competence, while limiting opportunities for inflammatory damage. This proposal focuses on an important component of this balance, the regulatory T cell. The search for regulatory T cell functions, their origin, and their potential for therapeutic application, is addressed in the proposed experiments.