Impairment of Mature B Cell Maintenance upon Combined Deletion of the Alternative NF-κB Transcription Factors RELB and NF-κB2 in B Cells.
Impairment of Mature B Cell Maintenance upon Combined Deletion of the Alternative NF-κB Transcription Factors RELB and NF-κB2 in B Cells.
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DOI：
10.4049/jimmunol.1501120
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发表时间：
2016-03-15
期刊：
影响因子：
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通讯作者：
Klein U
中科院分区：
文献类型：
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作者：
De Silva NS;Silva K;Anderson MM;Bhagat G;Klein U
B细胞活化因子（BAFF）对成熟B细胞的存活和成熟至关重要。BAFF通过BAFF受体（BAFFR）激活B细胞中的多种信号传导途径，包括替代核因子-κB（NF-κB）途径。转录因子RELB和NF-κB2（p100/p52）是旁路途径的下游介质;然而，这些NF-κB亚基的B细胞内在功能尚未单独或联合使用条件等位基因进行体内研究。我们在这里报告，B细胞特异性删除relB导致只有轻微的下降，在部分成熟的脾B细胞，而删除nfkb 2引起显着减少。这种表型在relb和nfkb 2的组合缺失后进一步恶化，并且最显著地影响边缘区B细胞的维持。与CD 40活化相反，BAFF刺激不能在体外拯救relb/nfkb 2缺失的B细胞。BAFF刺激的nfkb 2缺失与正常B细胞的RNA测序分析表明，替代NF-κB途径除了在BAFF介导的细胞存活中发挥关键作用外，还可能控制参与B细胞在淋巴微环境中定位和T细胞-B细胞相互作用建立的基因表达。因此，通过在B细胞中特异性地消融替代NF-κB途径的下游转录因子，我们在此确定了RELB和NF-κB2亚基在B细胞稳态中的组合活性的关键作用，其在生理条件下不能被经典NF-κB途径补偿。
B-cell activating factor (BAFF) is critical for the survival and maturation of mature B-cells. BAFF, via the BAFF receptor (BAFFR), activates multiple signaling pathways in B-cells, including the alternative nuclear factor-κB (NF-κB) pathway. The transcription factors RELB and NF-κB2 (p100/p52) are the downstream mediators of the alternative pathway; however, the B-cell-intrinsic functions of these NF-κB subunits have not been studied in vivo using conditional alleles, either individually or in combination. We here report that B-cell-specific deletion of relb led to only a slight decrease in the fraction of mature splenic B cells, whereas deletion of nfkb2 caused a marked reduction. This phenotype was further exacerbated upon combined deletion of relb and nfkb2 and most dramatically affected the maintenance of marginal zone B-cells. BAFF-stimulation, in contrast to CD40-activation, was unable to rescue relb/nfkb2-deleted B-cells in vitro. RNA-sequencing analysis of BAFF-stimulated nfkb2-deleted vs. normal B-cells suggests that the alternative NF-κB pathway, in addition to its critical role in BAFF-mediated cell survival, may control the expression of genes involved in the positioning of B-cells within the lymphoid microenvironment and in the establishment of T-cell-B-cell interactions. Thus, by ablating the downstream transcription factors of the alternative NF-κB pathway specifically in B-cells, we here identify a critical role for the combined activity of the RELB and NF-κB2 subunits in B-cell homeostasis that cannot be compensated for by the canonical NF-κB pathway under physiological conditions.