IAG7 ON SELECTING AUTOREACTIVE T CELLS

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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.