The major histocompatibility complex (MHC) class II locus is strongly associated with the risk of type 1 diabetes, and tissue specificity of the autoimmunity causing diabetes is likely to be determined by the trimolecular complex composed of an MHC molecule, an antigen, and a T cell receptor (TCR). We hypothesize that the interactions between components of this trimolecular complex, all of which are encoded in the germline, determines the nature of T cells involved in the development of type 1 diabetes. Targeting of an insulin B chain 9-23 amino acid peptide (insulin B:9-23) is highly likely to be an essential determinant in the initiation of islet inflammation in the spontaneous diabetes animal model, NOD mouse. We recently discovered that TCRs containing the germline-encoded variable gene (Vgene) sequence called """"""""TRAV5D-4"""""""" play a critical role to induce anti-islet autoimmunity via the recognition of insulin B:9-23 peptide. Thus, the trimolecular complex consisting of the insulin B:9-23 peptide and TRAV5D-4 TCR alpha chain plays a key role in developing anti-islet autoimmunity;however, how T cells expressing TRAV5D-4 TCRs contribute to the initiation and development of the disease remains to be elucidated. Given evidence that the DQ8 diabetes- susceptible HLA class II molecule is an ortholog of NOD I-Ag7 presenting the insulin B:9-23 peptide and that T cells expressing TRAV13-1 (human ortholog of TRAV5D-4) TCR alpha chains dominantly exist in the pancreas of a type 1 diabetes patient having DQ8, the ultimate goal of this proposal is to verify a proof of concept that insulin targetig by a specific germline-encoded TCR Vgene motif plays a critical role in the development of islet autoimmunity. In this proposal, we aim to determine the molecular mechanism of how TCRs, in particular those containing TRAV5D-4, target the critical peptide, insulin B:9-23, to initiate isle inflammation using the NOD mouse model (Aim 1), and to determine whether T cells expressing TRAV5D-4 are essential for diabetes development in NOD mice (Aim 2). If the development of anti-islet autoimmunity is completely suppressed in the absence of TRAV5D-4, targeting only T cells expressing such essential TRAV genes will enable us to develop a robust immunotherapy with the minimum of side effects. Finally, we will pursue the hypothesis that there is a conceptually similar interaction in the human trimolecular complex consisted of the insulin B:9-23 peptide and TRAV13-1 TCR Vgene motif underlying susceptibility to human type 1 diabetes (Aim 3). Findings from this proposal will provide a deeper understanding of the principles underlying the initiation of islet autoimmunity via the interaction within the insulin trimolecular complex, which will ultimately to be applied to design antigen-based immunodiagnostic and immunotherapeutic clinical studies for type 1diabetes in humans!
The proposed research will enhance our understanding of the mechanism how our own tissues are destroyed by the immune system and ultimately why autoimmune diseases occur. The knowledge gained by this proposal will lead us to develop therapies to prevent and cure autoimmune diseases such as type 1 diabetes.
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