Abstract
The MHC is the largest genetic risk factor for autoimmunity. It imposes risk in association with a complementary autoantigen specific TCR repertoire. How this occurs is unresolved. Each individual’s TCR repertoire is largely unique, and should therefore not contribute to population-wide disease risk. However, due to biases in TCR recombination, a subset of α and β sequences are shared by most individuals, or public. If these public α or β chains modulate a TCRαβ heterodimer’s likelihood of productively engaging autoantigen-MHC, they could influence autoimmune susceptibility. We demonstrate that disease-associated regulatory and effector TCRβ repertoires in autoimmune encephalomyelitis preferentially incorporate public TCR. Some disease-associated public TCRβ, when transgenically expressed, could further endow T cells with autoantigen specificity in the absence of priming, and demonstrate a subordinate role of the non-shared, endogenous TCRα chains in autoantigen specificity. Further, 2 of 7 Tg public and 0 of 7 Tg private TCRβ isolated from high frequency CNS-infiltrating T cells, provoked spontaneous, early-onset autoimmunity when associated with endogenous TCRα. These findings support a disproportionate contribution of public TCR to immunopathology and implicate them, in association with risk-associated MHC, in disease susceptibility. They further suggest that subsets of public sequences may serve as disease-specific biomarkers or therapeutic targets in autoimmunity.
