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

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.