Differential requirements for the canonical NF-κB transcription factors c-REL and RELA during the generation and activation of mature B cells

Signaling through the canonical nuclear factor‐κB (NF‐κB) pathway is critical for the generation and maintenance of mature B cells and for antigen‐dependent B‐cell activation. c‐REL (rel) and RELA (rela) are the downstream transcriptional activators of the canonical NF‐κB pathway. Studies of B cells derived from constitutional rel knockout mice and chimeric mice repopulated with rela–/– fetal liver cells provided evidence that the subunits can have distinct roles during B‐cell development. However, the B cell‐intrinsic functions of c‐REL and RELA during B‐cell generation and antigen‐dependent B‐cell activation have not been determined in vivo. To clarify this issue, we crossed mice with conditional rel and rela alleles individually or in combination to mice that express Cre‐recombinase in B cells. We here report that, whereas single deletion of rel or rela did not impair mature B‐cell generation and maintenance, their simultaneous deletion led to a dramatic reduction of follicular and marginal zone B cells. Upon T cell‐dependent immunization, B cell‐specific deletion of the c‐REL subunit alone abrogated the formation of germinal centers (GCs), whereas rela deletion did not affect GC formation. T‐independent responses were strongly impaired in mice with B cell‐specific deletion of rel, and only modestly in mice with RELA‐deficient B cells. Our findings identify differential requirements for the canonical NF‐κB subunits c‐REL and RELA at distinct stages of mature B‐cell development. The subunits are jointly required for the generation of mature B cells. During antigen‐dependent B‐cell activation, c‐REL is the critical subunit required for the initiation of the GC reaction and for optimal T‐independent antibody responses, with RELA being largely dispensable at this stage.