IAG7 ON SELECTING AUTOREACTIVE T CELLS

描述(改编自申请人的摘要)：某些等位基因形式 第二类主要组织相容性复合体(MHC)分子紧密相连 与人类和小鼠的自身免疫性或I型糖尿病有关。 这些分子共享独特且明确的物理和生物特性， 然而，它们如何影响糖尿病的发展尚不完全清楚。 但很明显，这些等位基因在塑造CD4+T细胞方面起着至关重要的作用 细胞池本身在调节疾病方面起着关键作用。点头鼠标 是一种优秀的、广泛应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)与 糖尿病。生化研究表明，I-A(G7)是一种例外 多肽结合力差，与增强的自身反应外周有关 T细胞池。从机制上讲，I-A(G7)如何促进 自身反应性T细胞尚不完全清楚。工作假说 表明I-A(G7)较差的结合性能--其特征是 多肽结合的快速失败率干扰胸腺负选择 发育中的T细胞，从而允许T细胞与 天生高度的自身抗原反应性。这项提议的目标是 检测I-A(G7)表达是否允许自身反应性T细胞逃逸 来自胸腺的另一种更强大的肽结合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)-在他们的 结合、呈递和删除发育中的胸腺细胞的能力 新的自我抗原。本研究提出以下目标：1)量化 糖尿病相关I-A(G7)分子的多肽结合能力 与抗糖尿病的I-A(D)分子结合到一个共同的抗原上。2) 建立II类稳定性与T细胞耐受性的相关性 规定的抗原性剂量。3)确定两者的关系 多肽结合稳定性与特异性抗原反应性T的缺失 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.