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 on co-stimulation are incompletely understood. Nr4a1 – 3 encode a small family of orphan nuclear receptors that are rapidly induced by B cell antigen receptor stimulation. Here, we show 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 the 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. Antigen-activated B cells are short lived in the absence of a second signal provided by CD4 + T cells or cytokines. Zikherman and colleagues report that the NR4A family of nuclear receptors (NUR77 and NOR-1) are responsible for enforcing this ‘tolerance’ to self-antigen (signal 1 only) and explain, in part, why B cells are dependent upon a second signal.