Differential requirements for the canonical NF-κB transcription factors c-REL and RELA during the generation and activation of mature B cells.
Differential requirements for the canonical NF-κB transcription factors c-REL and RELA during the generation and activation of mature B cells.
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DOI：
10.1038/icb.2016.95
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发表时间：
2017-03
影响因子：
4
通讯作者：
Klein U
中科院分区：
文献类型：
--
作者：
Milanovic M;Heise N;De Silva NS;Anderson MM;Silva K;Carette A;Orelli F;Bhagat G;Klein U
通过经典NF-κB途径的信号传导对于成熟B细胞的产生和维持以及抗原依赖性B细胞活化至关重要。c-REL（rel）和RELA（rela）是经典NF-κB通路的下游转录激活因子。对来自体质性rel敲除小鼠和用rela−/−胎肝细胞重新填充的嵌合小鼠的B细胞的研究提供了证据，表明亚基在B细胞发育过程中可能具有不同的作用。然而，在B细胞生成和抗原依赖性B细胞活化过程中，c-REL和RELA的B细胞内在功能尚未在体内确定。为了澄清这个问题，我们将具有条件性rel和rela等位基因的小鼠单独或组合地与在B细胞中表达Cre重组酶的小鼠杂交。我们在这里报告，而单一的删除rel或rela不损害成熟的B细胞的产生和维护，同时删除导致滤泡和边缘区B细胞的急剧减少。在T细胞依赖性免疫后，单独的c-REL亚基的B细胞特异性缺失废除了生发中心（GC）的形成，而rela缺失不影响GC的形成。在B细胞特异性缺失rel的小鼠中，T非依赖性反应受到严重损害，而在RELA缺陷B细胞的小鼠中，T非依赖性反应仅受到适度损害。我们的研究结果确定了在成熟B细胞发育的不同阶段对典型NF-κB亚基c-REL和RELA的不同需求。这些亚基是产生成熟B细胞所共同需要的。在抗原依赖性B细胞活化过程中，c-REL是启动GC反应和最佳T非依赖性抗体应答所需的关键亚基，RELA在此阶段主要被抑制。
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.