Treg and Antigen Presentation in Autoimmunity

描述（由申请人提供）： 候选人费博士。Shih是华盛顿大学儿科系流变学分部的教员。施博士对自身免疫性疾病有着长期的兴趣。她的最终目标是成为自身免疫领域的独立研究者，并从事转化研究，将她的实验室研究应用于患者护理。为了实现这一目标，她正在研究KRN小鼠的T细胞自身免疫性，KRN小鼠是类风湿性关节炎的小鼠模型。胸腺缺失是自身反应性T细胞从功能细胞库中消除的主要机制。在KRN小鼠中，对普遍存在的自身抗原葡萄糖-6-磷酸异构酶（GPI）具有特异性的KRN T细胞的不完全缺失通过向抗GPI B细胞提供T细胞帮助而导致其活化和关节炎。在MHC II启动子下的KRN TCR激动剂的转基因表达导致胸腺缺失，抗GPIT和B细胞应答丧失，关节炎病程减弱。然而，双转基因小鼠死于全身性自身免疫，多器官炎症和自身抗体产生。广泛的胸腺缺失导致淋巴细胞减少和CD 4 + CD 25+调节性T细胞（TCR）的消除，但保留了一些表达内源性TCR的CD 4 + T细胞，其在外周寡克隆扩增。疾病通过这些T细胞转移，并通过CD 4 + CD 25 + T细胞的共转移来预防。该提案采用双管齐下的方法来阐明全身性T细胞自身反应性可导致从关节中心性滑膜炎到暴发性多器官炎症的多种疾病表型的机制。特异性目的1研究了TcB在致病性T细胞的运输、生长和获得效应子功能中的作用。具体目标2询问的能力 不同的抗原呈递细胞（在稳态下和在炎症期间）呈递GPI，以及这将如何影响KRN小鼠中疾病的起始和传播。

DESCRIPTION (provided by applicant): The candidate, Dr. Fei F. Shih, is a faculty member in the Rheumatology Division, Department of Pediatrics at Washington University. Dr. Shih has a long standing interest in autoimmune diseases. Her ultimate goal is to become an independent investigator in the field of autoimmunity and engage in translational research to apply her bench research to patient care. To achieve this goal she is examining T cell autoimmunity in KRN mice, a murine model of rheumatoid arthritis. Thymic deletion is the major mechanism whereby autoreactive T cells are eliminated from the functional cell repertoire. In KRN mice, incomplete deletion of KRN T cells with specificity for the ubiquitous self-antigen glucose-6-phosphate-isomerase (GPI) resulted in their activation and arthritis through provision of T cell help to anti-GPI B cells. Transgenic expression of a KRN TCR agonist under the MHC II promoter resulted in thymic deletion with loss of anti-GPI T and B cell responses and attenuated arthritis course. However, double transgenic mice succumbed to systemic autoimmunity with multi-organ inflammation and autoantibody production. Extensive thymic deletion resulted in lymphopenia and elimination of CD4+CD25+ regulatory T cells (Tregs), but spared some CD4+ T cells expressing endogenous TCR which oligoclonally expanded in the periphery. Disease was transferred by these T cells and prevented by co-transfer of CD4+CD25+ Tregs. This proposal employs a two-prong approach to elucidate the mechanisms whereby systemic T cell autoreactivity can result in diverse disease phenotype from joint centered synovitis to a fulminant multi-organ inflammation. Specific Aim 1 investigates the role of Tregs in the trafficking, growth, and the acquisition of effector function by pathogenic T cells. Specific Aim 2 interrogates the capacity of different antigen presenting cells (under steady state and during inflammation) to present GPI and how this will affect the initiation and propagation of disease in KRN mice.