Dual TCRα expression alters agonist selection, redirecting Treg-biased insulin-specific thymocytes into the conventional T cell lineage

Abstract

Abstract Despite accounting for ~10% of the T cell population in mice and humans, the role of dual TCR-expressing T cells in immunity remains poorly understood. It has been hypothesized that dual TCR T cells pose an “autoimmune hazard” by allowing self-reactive TCRs to escape negative selection. We revisited this hypothesis using the non-obese diabetic (NOD) mouse model of type 1 diabetes (T1D). We bred NOD mice hemizygous at both TCRα and β (TCRα+/− β+/−) loci, rendering them incapable of producing dual TCR T cells. We found that NOD mice lacking dual TCRα expression were resistant to developing diabetes resulting from an increased insulin-specific Treg:Tconv ratio. Furthermore, early depletion of CD25-expressing cells was sufficient to induce diabetes in single TCR T cell NOD mice demonstrating that these mice are capable of developing diabetes and that Treg cells are responsible for their observed resistance to diabetes. Further investigation uncovered a previously-unrecognized impact of dual TCRα expression on agonist selection. Specifically, we found in single TCR T cell mice that single positive (SP) thymocytes had a higher Treg:CD4 ratio indicating increased Treg commitment, that insulin-specific thymocytes exhibited higher CD5 expression suggesting increased TCR signaling, and that deletion of SP thymocytes was reduced. Altogether these data demonstrate that dual TCRα expression perturbs agonist selection of the insulin-specific thymocyte subset, resulting in skewing of this population toward the diabetogenic conventional CD4+ T cell lineage and away from the regulatory T cell lineage. Thus, dual TCR expression can promote autoimmunity by reducing the ratio of protective Treg cells to pathogenic T cells.