Negative feedback by NUR77/Nr4a1 restrains B cell clonal dominance during early T-dependent immune responses

Cell Rep. 2021 Aug 31;36(9):109645. doi: 10.1016/j.celrep.2021.109645.


B cell clones compete for entry into and dominance within germinal centers (GCs), where the highest-affinity B cell receptors (BCRs) are selected. However, diverse and low-affinity B cells can enter and reside in GCs for extended periods. To reconcile these observations, we hypothesize that a negative feedback loop may operate within B cells to preferentially restrain high-affinity clones from monopolizing the early GC niche. Here, we report a role for the nuclear receptor NUR77/Nr4a1 in this process. We show that NUR77 expression scales with antigen stimulation and restrains B cell expansion. Although NUR77 is dispensable for regulating GC size when GCs are elicited in a largely clonal manner, it serves to curb immunodominance under conditions where diverse clonal populations must compete for a constrained niche. We propose that this is important to preserve early clonal diversity in order to limit holes in the post-immune repertoire and to optimize GC selection.

Keywords: B cell; NUR77; Nr4a1; clonal competition; clonal diversity; germinal center; humoral immune response; immunodominance.

Publication types

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

MeSH terms

  • Animals
  • B-Lymphocytes / drug effects
  • B-Lymphocytes / immunology
  • B-Lymphocytes / metabolism*
  • Cell Proliferation
  • Cells, Cultured
  • Clonal Selection, Antigen-Mediated
  • Feedback, Physiological
  • Female
  • Germinal Center / drug effects
  • Germinal Center / immunology
  • Germinal Center / metabolism*
  • Immunity, Humoral* / drug effects
  • Immunization
  • Immunodominant Epitopes*
  • Lymphocyte Activation
  • Male
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nuclear Receptor Subfamily 4, Group A, Member 1 / genetics
  • Nuclear Receptor Subfamily 4, Group A, Member 1 / metabolism*
  • Signal Transduction
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism*
  • Vaccines, Synthetic / administration & dosage


  • Immunodominant Epitopes
  • Nr4a1 protein, mouse
  • Nuclear Receptor Subfamily 4, Group A, Member 1
  • Vaccines, Synthetic