期刊
IMMUNOLOGY AND CELL BIOLOGY
卷 95, 期 3, 页码 261-271出版社
WILEY
DOI: 10.1038/icb.2016.95
关键词
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资金
- NCI/NIH [R01-CA157660]
- Stewart Trust Foundation (USA)
- HICCC
- German Research Council (DFG)
- Cancer Biology Training Program fellowship (NCI/NIH) [5T32-CA009503-26]
Signaling through the canonical nuclear factor-B-k ( NF-B-k) 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-B-k 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-B-k 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.
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