Nur77 Regulates Nondeletional Mechanisms of Tolerance in T Cells

Abstract

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 BimNur77 mice exhibited comparable accumulation of high-affinity signaled CD4CD8 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 Foxp3FR4CD73 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.

Role of the Orphan Nuclear Receptor NR4A Family in T-Cell Biology

“…Nevertheless, deficiency in both NR4A1 and Bim led to enhanced efficiency of positive selection in female mice bearing the MHC I-restricted HY cd4 transgene ( 18 ) and NR4A1 deficiency alone resulted in increased positive selection in the OT-II TCR transgenic model ( 46 ). However, NR4A1 deficiency did not enhance positive selection in the OT-I transgenic model ( 19 ). Overall, the contribution of NR4A1 to positive selection requires further examination and remains unclear, though its influence may vary with selection circumstances including lineage commitment and the intrinsic self-reactivity of transgenic TCR models investigated.…”

“…This is further emphasized by emerging evidence suggesting that the induction of individual NR4A family members is differentially regulated downstream of TCR signaling ( 15 ). Added complexity stems from the fact that the function of NR4A family members during thymocyte development has been reported to be dependent on transactivation ( 16 – 19 ) or extra-nuclear activities ( 20 – 23 ) ( Figure 1 ). Finally, this section will focus on the role of the NR4A family in αβ-thymocyte selection, since to our knowledge the NR4As have not been reported to regulate the development of any other thymic lineages.…”

“…Single deficiency in either NR4A1 or Bim did not result in broken tolerance, however, combined deficiency resulted in broken self-tolerance signified by the development of diabetes. Since the number of mature OT-I thymocytes and T cells was similar in Bim-deficient and NR4A1/Bim doubly deficient situations, the break in tolerance suggests NR4A1 regulates tolerance through altering the functional capabilities of the thymocytes or T cells ( 19 ). A role for NR4A3 and redundancy between NR4A1 and NR4A3 has not been investigated in a medullary antigen-specific model system.…”

Glucocorticoids Oppose Thymocyte Negative Selection by Inhibiting Helios and Nur77

“…In contrast, Nur77 has been implicated in negative selection of SP cells by medullary tissue-restricted Ags. Nur77 deficiency in OT-II and OT-I TCR transgenics rescued SP thymocytes from negative selection induced by transgenic expression of their cognate Ag, OVA (23,24). The self-peptides that mediate positive selection of the AND TCR on the H-2 b MHC background used in this study are unknown, but it is plausible that, in addition to being expressed in the cortex, they are expressed in the medulla, where they could serve as negatively selecting ligands for SP thymocytes lacking the GR.…”

‘Nur'turing tumor T cell tolerance and exhaustion: novel function for Nuclear Receptor Nur77 in immunity

“…Given that Nur77 has a strong anti‐inflammatory function both in the adaptive immune system and is protective in autoimmune diseases, major side effects may be expected when chronically inhibiting Nur77. More specifically, Nur77 has a beneficial influence on auto‐immune diseases [91], atherosclerosis [92,93], MS [94], inflammatory bowel disease [13,89], and inflammatory lung disease [95]. These diseases all worsen in Nur77‐deficient mice and involve chronic inflammation.…”