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

  • Author(s): Tan, Corey;
  • Hiwa, Ryosuke;
  • Mueller, James L;
  • Vykunta, Vivasvan;
  • Hibiya, Kenta;
  • Noviski, Mark;
  • Huizar, John;
  • Brooks, Jeremy F;
  • Garcia, Jose;
  • Heyn, Cheryl;
  • Li, Zhongmei;
  • Marson, Alexander;
  • Zikherman, Julie
  • et al.
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 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.

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