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形成自身反应性T细胞谱系的关键事件。为此，我们将开发一种新的模型系统，在该系统中，将不同年龄的NOD雌性小鼠的胸腺移植到NOD受体的肾被膜下，导致外周T细胞重建。从胎儿和新生儿结节捐赠者制备的胸腺产生具有1型表型特征的CD4+和CD8+T细胞。重要的是，NOD.SCID的接受者除了甲状腺炎外，还会患上明显的糖尿病。与之形成鲜明对比的是，将4周或更大的NOD供者的胸腺移植到NOD小鼠身上，小鼠患上了严重的结肠炎，但仍然没有糖尿病和甲状腺炎。我们假设，年龄相关的事件调节胸腺正负选择的有效性，而胸腺正负选择反过来促进致病T前体的时间发展。已经建立了三个特定的目标来确定调节T细胞组织特异性的时间发育的机制。第一个将确定与年龄相关的胸腺事件如何塑造自身反应性T前体的谱系。第二个特定目标将确定胸腺中正在进行的细胞事件，这些事件介导T前体的时间发展，介导自身免疫和结肠炎。最终的特定目标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作用。通过这种方式，将获得对塑造自身反应性胸腺细胞谱系的关键事件的新见解。 公共卫生相关性：1型糖尿病和其他组织特异性自身免疫性疾病是由T细胞介导的。然而，促进自身反应性T细胞发育的关键事件仍然知之甚少。这项建议使用了一个新的模型系统来定义细胞和分子事件，这些事件调节胸腺中自身反应性T前体的发展。

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.