IAG7 ON SELECTING AUTOREACTIVE T CELLS

描述（改编自申请人的摘要）： II类主要组织相容性复合体（MHC）分子紧密地 与人类和小鼠的自身免疫性或I型糖尿病有关。 这些分子具有独特和明确的物理和生物学特性， 然而，它们如何影响糖尿病的发展尚不完全清楚。 但很明显，这些等位基因在形成CD 4 + T细胞中起着至关重要的作用。 细胞池本身在介导疾病中至关重要。 NOD小鼠 是一种优秀的、广泛使用的人类糖尿病模型。 NOD小鼠研究 支持其MHC II类分子I-A（g7）之间的连接， 糖尿病 生物化学研究表明，I-A（g7）是一种特殊的 肽的结合力差，并与增强的自身反应性外周 T细胞池。 从机制上讲，国际援助（g7）如何促进 自身反应性T细胞尚未完全了解。 工作假设 表明I-A（g7）的不良结合性质-特征在于 肽结合的快速解离速率干扰胸腺阴性选择 的发育中的T细胞，从而允许输出的T细胞， 自身抗原反应性高。 本提案的目的是 测试I-A（g7）表达是否允许自身反应性T细胞逃逸 其他更强的肽结合II类分子 会删除。 这些实验旨在比较两个密切相关的， 但在生物化学上不同的II类分子I-A（g7）和I-A（d）中， 能够将发育中的胸腺细胞结合、呈现和删除到已知的 新自身抗原 本研究提出以下目标：1）量化 糖尿病相关I-A（g7）分子的肽结合能力 与抗糖尿病的I-A（d）分子结合。 （二） 确定II类稳定性和T细胞耐受性的相关性， 确定的抗原剂量。 3)确定之间的关系 肽结合稳定性和特异性抗原反应性T 细胞受体

DESCRIPTION (adapted from applicant's abstract): Certain allelic forms of the class II major histocompatibility complex (MHC) molecules are tightly linked with autoimmune or type I diabetes mellitus in humans and mice. These molecules share unique and defined physical and biological properties, yet how they influence the development of diabetes is not fully understood. But it is clear that these alleles play a vital role in shaping the CD4+ T cell pool that is itself critical in mediating the disease. The NOD mouse is an excellent, widely used model of human diabetes. NOD mouse studies support the connection between its MHC class II molecule, I-A(g7), and diabetes. Biochemical studies have shown that I-A(g7) is an exceptionally poor binder of peptides and is linked to an enhanced autoreactive peripheral T cell pool. Mechanistically, how I-A(g7) facilitates the emergence of autoreactive T cells is not fully understood. The working hypothesis suggests that the poor binding properties of I-A(g7)-characterized by the fast off-rate of peptide binding interferes with thymic negative selection of the developing T cells, thereby allowing the exportation of T cells with intrinsically high self-antigen reactivity. The goal of this proposal is to test whether I-A(g7) expression permits the escape of autoreactive T cells from the thymus that other, more robust peptide-binding class II molecules would delete. The experiments are designed to compare two closely related, but biochemically-distinct, class II molecules I-A(g7) and I-A(d)- in their ability to bind, present and delete developing thymocytes to a known neo-self-antigen. Following aims are proposed in this study: 1) Quantify the peptide binding capacity of the diabetes-associated I-A(g7) molecule with the diabetes-resistant I-A(d) molecule to a shared antigen. 2) Establish the relatedness of class II stability and T cell tolerance at defined antigenic doses. 3) Determine the relationship between peptide-binding stability and the deletion of specific antigen reactive T cell receptors.