Age-Dependent Thymic Events and the Development of Autoimmune T Cells in NOD Mice

描述（由申请人提供）：本提案的目标是定义胸腺中正在进行的塑造自身反应性T细胞库的关键事件。为此，我们将建立一种新的模型系统，将不同年龄NOD雌性小鼠的胸腺移植到NOD的肾包膜下。scid受体导致外周T细胞重构。由胎儿和新生儿NOD供体制备的胸腺产生CD4+和CD8+ T细胞，其特征为1型表型。重要的是点头。Scid受者除甲状腺炎外，还会出现明显的糖尿病。与之形成鲜明对比的是NOD。移植了4周大或更大的NOD供体胸腺的scid小鼠出现了严重的结肠炎，但没有糖尿病和甲状腺炎。我们假设年龄依赖性事件调节胸腺阳性和阴性选择的功效，进而促进致病性T前体的时间发展。已经建立了三个特异性目标来确定调节T细胞组织特异性时间发育的机制。第一个将确定年龄依赖性胸腺事件如何塑造自身反应性T前体的曲目。第二个特异性目标将确定胸腺中正在进行的细胞事件，这些细胞事件介导T前体介导自身免疫和结肠炎的时间发育。最后的特异性目的将确定遗传背景和胸腺表达的组织抗原在组织特异性T细胞的时间发育中的贡献。通过这种方式，将获得对形成自身反应性胸腺细胞库的关键事件的新见解。

DESCRIPTION (provided by applicant): The goal of this proposal is to define the key events ongoing in the thymus that shape the repertoire of autoreactive T cells. For this purpose, we will exploit a novel model system in which thymi from NOD female mice of varying ages are transplanted under the kidney capsule of NOD.scid recipients resulting in T cell reconstitution of the periphery. Thymi prepared from fetal and newborn NOD donors produce CD4+ and CD8+ T cells characterized by a type 1 phenotype. Importantly, the NOD.scid recipients develop overt diabetes, in addition to thyroiditis. In marked contrast, NOD.scid mice transplanted with thymi from 4 week-old or older NOD donors develop severe colitis but remain free of diabetes and thyroiditis. We hypothesize that age- dependent events regulate the efficacy of thymic positive and negative selection that in turn promote the temporal development of pathogenic T precursors. Three Specific Aims have been established to determine the mechanisms regulating the temporal development of T cell tissue-specificity. The first will determine how age-dependent thymic events shape the repertoire of autoreactive T precursors. The second Specific Aim will determine the cellular events ongoing in the thymus that mediate the temporal development of T precursors mediating autoimmunity and colitis. The final Specific Aim will ascertain the contribution of genetic background and thymic expressed tissue antigens in the temporal development of tissue-specific T cells. In this way, novel insight will be gained into the critical events that shape the repertoire of autoreactive thymocytes. PUBLIC HEALTH RELEVANCE: Type 1 diabetes and other tissue-specific autoimmune diseases are mediated by T cells. The critical events that promote development of autoreactive T cells, however, remain poorly understood. This proposal employs a novel model system to define the cellular and molecular events that regulate the development of autoreactive T precursors in the thymus.