Increased Nur77 is disconnected from TCR affinity in insulin-specific Tregs.

Foxp3+ regulatory T cells (Tregs) are capable suppressors of aberrant self-reactivity. However, how differences in affinity and specificity may support Treg function compared with autoimmune T cell function remains unresolved. In this study, we analyzed the T cell receptor (TCR) repertoires of the regulatory and effector T cells that spontaneously infiltrate pancreatic islets of nonobese diabetic mice and therefore share antigen specificity. Using 2-dimensional micropipette measurements of TCR affinity, we show that effector and regulatory T cell-derived TCRs possess similar wide-ranging affinities for self-antigen. Treg-derived TCRs conferred variable protective function and Treg suppressive capacity was, in part, determined by the relative antigen-reactivity of effector T cells. Interestingly, when expressing the same TCR, Tregs showed higher Nur77-GFP expression than effector T cells in vivo, suggesting a Treg-intrinsic ability to compete for antigen. In vitro, we observed accelerated Treg TCR activation, suggesting that Tregs are poised for faster response to antigen than T effectors. Our findings expose a subpopulation of Tregs possessing low-affinity, suboptimal TCRs, obscured by apparent higher Nur77 expression in Tregs as a whole.