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

Nat Immunol. 2020 Oct;21(10):1267-1279. doi: 10.1038/s41590-020-0765-7. Epub 2020 Aug 31.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • B-Lymphocytes / immunology*
  • Cell Communication
  • Cell Proliferation
  • Cells, Cultured
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Immunity, Humoral
  • Immunomodulation
  • Lymphocyte Activation
  • Mice
  • Mice, Knockout
  • Nuclear Receptor Subfamily 4, Group A, Member 1 / genetics
  • Nuclear Receptor Subfamily 4, Group A, Member 1 / metabolism*
  • Receptors, Antigen, B-Cell / metabolism
  • Receptors, Steroid / genetics
  • Receptors, Steroid / metabolism
  • Receptors, Thyroid Hormone / genetics
  • Receptors, Thyroid Hormone / metabolism
  • Signal Transduction
  • T-Lymphocytes, Helper-Inducer / immunology*


  • DNA-Binding Proteins
  • NR4A3 protein, human
  • Nr4a1 protein, mouse
  • Nuclear Receptor Subfamily 4, Group A, Member 1
  • Receptors, Antigen, B-Cell
  • Receptors, Steroid
  • Receptors, Thyroid Hormone