Transcription factors of the alternative NF-κB pathway are required for germinal center B-cell development
Transcription factors of the alternative NF-κB pathway are required for germinal center B-cell development
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DOI：
10.1073/pnas.1602728113
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发表时间：
2016-08-09
影响因子：
11.1
通讯作者：
Klein, Ulf
中科院分区：
文献类型：
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作者：
De Silva, Nilushi S.;Anderson, Michael M.;Klein, Ulf
NF-κ B信号级联传递B细胞生长和存活所必需的外部信号。这种级联反应经常被由生发中心（GC）B细胞恶性转化引起的癌症所劫持，这强调了破译NF-κ B在这些细胞中的功能的重要性。NF-κ B信号级联由两个分支组成，即经典和替代NF-κ B途径，由不同的转录因子介导。替代途径的转录因子RELB和NF-κ B2在B细胞发育后期的表达和功能还不完全清楚。在GC B细胞中使用relB和nfkb 2的条件性缺失，我们在这里报告，RELB和NF-κ B 2的消融，而不是单个转录因子的消融，导致已建立的GC的崩溃。GC B细胞中的RELB/NF-κ B2缺陷与受损的细胞周期进入和细胞表面受体诱导的T细胞共刺激配体的表达减少相关，该配体促进B和T细胞之间的最佳相互作用。人扁桃体组织的分析显示，浆细胞及其前体细胞在GC中表达高水平的NF-κ B2相对于周围的淋巴细胞。因此，在鼠GC B细胞中nfkb 2的缺失导致抗原特异性抗体分泌细胞的显著减少，而relB的缺失没有影响。这些结果表明，替代NF-κ B途径的转录因子控制晚期B细胞发育的不同阶段，这可能对异常激活该途径的B细胞恶性肿瘤有影响。
The NF-kappa B signaling cascade relays external signals essential for B-cell growth and survival. This cascade is frequently hijacked by cancers that arise from the malignant transformation of germinal center (GC) B cells, underscoring the importance of deciphering the function of NF-kappa B in these cells. The NF-kappa B signaling cascade is comprised of two branches, the canonical and alternative NF-kappa B pathways, mediated by distinct transcription factors. The expression and function of the transcription factors of the alternative pathway, RELB and NF-kappa B2, in late B-cell development is incompletely understood. Using conditional deletion of relb and nfkb2 in GC B cells, we here report that ablation of both RELB and NF-kappa B2, but not of the single transcription factors, resulted in the collapse of established GCs. RELB/ NF-kappa B2 deficiency in GC B cells was associated with impaired cell-cycle entry and reduced expression of the cell-surface receptor inducible T-cell costimulator ligand that promotes optimal interactions between B and T cells. Analysis of human tonsillar tissue revealed that plasma cells and their precursors in the GC expressed high levels of NF-kappa B2 relative to surrounding lymphocytes. Accordingly, deletion of nfkb2 in murine GC B cells resulted in a dramatic reduction of antigen-specific antibody-secreting cells, whereas deletion of relb had no effect. These results demonstrate that the transcription factors of the alternative NF-kappa B pathway control distinct stages of late B-cell development, which may have implications for B-cell malignancies that aberrantly activate this pathway.