Absence of dual TCR T cells protects NOD mice from diabetes due to an increased insulin-specific Treg:Teff ratio

Abstract

Abstract Due to allelic exclusion, most αβ T cells express only a single αβ TCR specificity. However, around 10% of human and mouse T cells express two different α chains with the potential for dual specificities. Dual β-expressing T cells also exist and account for ~1% of all T cells. Expression of two different TCR specificities by a single T cell is one hypothesized mechanism by which self-reactive TCRs escape central tolerance to initiate autoimmunity. While peripheral tolerance mechanisms typically control any self-reactive T cells in healthy animals, these mechanisms are hypo-functional in NOD mice. We hypothesized that eliminating dual TCR T cells would protect NOD mice from diabetes. To test this hypothesis we generated NOD mice hemizygous at both the TCRα and β loci (TCRα+/−β+/−). Indeed, we found that NOD mice incapable of generating dual TCR T cells were protected from diabetes with both lower diabetes incidence than wildtype (WT) NOD mice (0% versus 70% at 30 weeks of age) and also lower insulitis scores at 10 weeks of age. Examination of the insulin-specific T cell population in the pancreas-draining lymph node revealed a lower Treg:Teff ratio in WT NOD mice compared to single TCR T cell NOD mice. Anti-PD-1 treatment resulted in the rapid development of diabetes in 100% of WT NOD mice but in only 30% of single TCR T cell mice, suggesting that the diabetes resistance phenotype of single TCR T cell mice is not primarily due to increased anergy. These data support the hypothesis that the presence of dual TCR T cells increases the risk of diabetes in NOD mice by altering the insulin-specific Treg:Teff ratio.