NR4A nuclear receptors restrain B cell responses to antigen when second signals are absent or limiting

Abstract

Antigen stimulation (signal 1) triggers B cell proliferation, and primes B cells to recruit, engage, and respond to T cell help (signal 2). Failure to receive signal 2 within a defined time window results in B cell apoptosis, yet the mechanisms that enforce dependence upon co-stimulation are incompletely understood. Nr4a1-3 encode a small family of orphan nuclear receptors that are rapidly induced by B cell antigen receptor (BCR) stimulation. Here we showed that Nr4a1 and Nr4a3 play partially redundant roles to restrain B cell responses to antigen in the absence of co-stimulation, and do so in part by repressing expression of BATF and consequently MYC. The NR4A family also restrains B cell access to T cell help by repressing expression of the T cell chemokines CCL3 and CCL4, as well as CD86 and ICAM1. Such NR4A-mediated regulation plays a role specifically under conditions of competition for limiting T cell help.

Regulation of layered T cell tolerance mechanisms by the NR4A family is essential to preserve immune homeostasis and suppress autoimmunity

“…Nearly complete redundancy between Nr4a1 and Nr4a3 are evident in Treg and during negative selection; deletion of both family members is necessary to unmask these roles. By contrast, regulation of B cell responses (27) and CD8 + T cell exhaustion (17) by the NR4A family appear additive. Based on published work (24) and our observations of the IL-2 module in SKO and DKO T cells, we speculate that regulation of CD4 + T cell anergy is similarly additive, but this remains to be fully addressed.…”

“…In addition, it is likely that NR4A factors also play important roles in counter-regulating acute as well as chronic inflammatory/immune stimuli and promoting a return to immune homeostasis. Indeed, negative feedback by NR4A restrain responses to LPS in myeloid cells (71) and to antigen stimulation in B cells (27).…”

“…Like other Treg deficient models, gDKO mice exhibit spontaneous polyclonal B cell activation and differentiation under steady-state conditions (Figures 4A, B, Supplementary Figures 4A-F). We previously reported that Nr4a1 expression scales with both acute and chronic antigen stimulation in B cells (21,22,27). More recently, we identified a cell-intrinsic role for the NR4A family in restraining Ag-induced B cell expansion when co-stimulatory signals are absent or limiting, including in the context of B cell tolerance (22,27).…”

“…Indeed, the NR4A family has been argued to play a tolerogenic role in all these contexts. The NR4A family selectively restrains the survival and expansion of B cells that encounter antigen (signal 1) in the absence of co-stimulation (signal 2) (22,27). Similarly, overexpression of either Nr4a1 or Nr4a3 mediates antigen-induced cell death in the thymus, while a dominant-negative transgenic (Tg) construct had the opposite effect (20,28,29).…”

NR4A1 suppresses cancer replication stress through R-loop-dependent inhibition of immediate early gene transcriptional elongation

“…However, our review of NR4A1 binding landscapes in these cells 29 , suggests predominant binding to the genebodies, rather than to the promoters of IEGs, consistent with the transcriptional elongation control described here. Most recently, NR4A1 was also reported to be one of the key factors to restrain B cell responses to antigen 30 . Taken all together, these observations point to potentially convergent mechanisms in immune and cancer cells, with NR4A1-mediated adaptation to chronic antigen stimulation leading to an exhaustion phenotype in immune cells, and NR4A1 -mediated tolerance to oncogene-driven replication stress preventing mitotic catastrophe in cancer cells.…”