Abstract
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.
Highlights
Since the initial discovery of regulatory T cells (Tregs) and their recognition as a distinct T cell lineage dependent upon the transcription factor FOXP3, it has been shown that they are essential for immune homeostasis and tolerance to self [1]
We found that negative selection of DKO thymocytes in competitive chimeras was profoundly impaired in a cell-autonomous manner
We recently identified a cell-intrinsic role for the NR4A family in restraining antigen-induced B cell expansion in the absence of costimulation, including in the context of B cell tolerance [15, 20]
Summary
Since the initial discovery of regulatory T cells (Tregs) and their recognition as a distinct T cell lineage dependent upon the transcription factor FOXP3, it has been shown that they are essential for immune homeostasis and tolerance to self [1]. Extensive cell-intrinsic mechanisms that operate in other immune cell lineages are essential to maintain tolerance to self, including processes such as deletion and hyporesponsiveness of self-reactive lymphocytes It has been difficult to isolate redundant functions of this family in other immune cell populations. This remains an important area to explore since the NR4A family are widely expressed and thought to be druggable targets that may facilitate manipulation of immune cell function in autoimmune disease, tumor immunotherapy, and hematologic malignancies [8,9,10,11]
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