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 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 (GC), 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.