T Cell Receptor Genotype and Determine Susceptibility to Rat Autoimmune Diabetes.

Genetic analyses of human type 1 diabetes (T1D) have yet to reveal a complete pathophysiologic mechanism. Inbred rats with a high-risk class II major histocompatibility complex (MHC) haplotype (RT1B/D) can illuminate such mechanisms. Using T1D-susceptible LEW.1WR1 rats that express RT1B/D and a susceptible allele of the promoter, we demonstrate that germline knockout of which encodes the Vβ13a T cell receptor β chain, completely prevents diabetes. Using the RT1B/D-identical LEW.1W rat, which does not develop T1D despite also having the same β chain gene but a different allele at the locus, we show that knockout of the regulatory gene renders these resistant rats relatively susceptible to diabetes. In silico structural modeling of the susceptible allele of the Vβ13a TCR and its class II RT1 ligand suggests a mechanism by which a germline TCR β chain gene could promote susceptibility to T1D in the absence of downstream immunoregulation like that provided by UBASH3A. Together these data demonstrate the critical contribution of the Vβ13a TCR to the autoimmune synapse in T1D and the regulation of the response by UBASH3A. These experiments dissect the mechanisms by which MHC class II heterodimers, TCR and regulatory element interact to induce autoimmunity.