NR4A family members regulate T cell tolerance to preserve immune homeostasis and suppress autoimmunity

The NR4A family of orphan nuclear receptors (Nr4a1-3) plays redundant roles to establish and maintain Treg identity; deletion of multiple family members in the thymus results in Treg deficiency and a severe inflammatory disease. Consequently, it has been challenging to unmask redundant functions of the NR4A family in other immune cells. Here we use a competitive bone marrow chimera strategy, coupled with conditional genetic tools, to rescue Treg homeostasis and unmask such functions. Unexpectedly, chimeras harboring Nr4a1(-/-) Nr4a3(-/-) (double-knockout, DKO) bone marrow developed autoantibodies and a systemic inflammatory disease despite a replete Treg compartment of largely WT origin. This disease differs qualitatively from that seen with Treg deficiency and is B cell extrinsic. Negative selection of DKO thymocytes is profoundly impaired in a cell-intrinsic manner. Consistent with escape of self-reactive T cells into the periphery, DKO T cells with functional, phenotypic, and transcriptional features of anergy accumulated in chimeric mice. Nevertheless, we observed upregulation of genes encoding inflammatory mediators in anergic DKO T cells, and DKO T cells exhibited enhanced capacity for IL-2 production. These studies reveal cell intrinsic roles for the NR4A family in both central and peripheral T cell tolerance and demonstrate that each is essential to preserve immune homeostasis.

Automated summary

The NR4A family of orphan nuclear receptors plays redundant roles in establishing and maintaining Treg identity, and deletion of family members leads to Treg deficiency and severe inflammatory diseases. Through a competitive bone marrow chimera strategy, it was discovered that DKO bone marrow chimeras developed autoantibodies and inflammatory diseases despite having a Treg compartment mostly from WT origin. This study highlights the essential cell intrinsic roles of the NR4A family in central and peripheral T cell tolerance, demonstrating their importance in immune homeostasis.