Nur77 Regulates Nondeletional Mechanisms of Tolerance in T Cells

Negative selection against highly self-reactive thymocytes is critical for preventing autoimmunity. Thymocyte deletion, anergy induction, and agonist selection are all forms of negative selection that can occur following a high-affinity TCR signal. Of Bim and Nur77, two TCR-induced proteins with proapoptotic function, Bim has been shown to be important for clonal deletion in several model systems, whereas Nur77 was often dispensable. However, Nur77 has been reported to influence other aspects of T cell development by mechanisms that may not be related to its proapoptotic function. In this study, we examined the role of Nur77 during thymocyte development in the presence and absence of Bim to separate apoptotic from nonapoptotic functions of Nur77. Polyclonal Bim^-/- and Bim^-/-Nur77^-/- mice exhibited comparable accumulation of high-affinity signaled CD4⁺CD8⁺ double-positive thymocytes and CD8⁺ and CD4⁺ single-positive thymocytes. However, combined Bim and Nur77 deficiency increased the frequency of thymic Foxp3⁺ T regulatory cells and Foxp3^-FR4^hiCD73^hi anergic phenotype CD4⁺ T cells compared with Bim^-/- mice, suggesting that Nur77 expression impairs the development of nonconventional tolerance-inducing cell fates. Using the OT-I RIP-mOVA model, we found that Nur77 deficiency did not substantially impact clonal deletion nor did it exacerbate the defect in clonal deletion in the absence of Bim. However, additional loss of Nur77 in the absence of Bim led to diabetes induction, suggesting that Nur77 promotes tolerance in this context. Together, these data reveal novel nondeletional roles for Nur77 that differ between T cell subsets and have implications for self-tolerance.