Canonical NF-κB signaling is uniquely required for the long-term persistence of functional mature B cells
Canonical NF-κB signaling is uniquely required for the long-term persistence of functional mature B cells
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DOI：
10.1073/pnas.1604529113
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发表时间：
2016-05-03
影响因子：
11.1
通讯作者：
Rajewsky, Klaus
中科院分区：
文献类型：
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作者：
Derudder, Emmanuel;Herzog, Sebastian;Rajewsky, Klaus
尽管规范的核因子-kappaB信号对于产生一个正常的成熟B细胞室是至关重要的，但它在静息的成熟B细胞的持久性中的作用是有争议的。为了解决这一矛盾，我们去除了核因子-kappa B必需调节物(NEMO)和I-kappa B激酶2(IKK2)，这是规范途径的两个基本介质，无论是在B细胞发育的早期还是在成熟的B细胞中。早期消融严重抑制了所有成熟B细胞亚群的产生，但滤泡B细胞数量可以通过异位表达B细胞淋巴瘤2(BCL2)而在很大程度上被挽救，尽管在过渡期仍存在阻碍。边缘带(MZ)B和B1细胞未被挽救，表明规范的NF-kappa B信号可能在这些亚群中超出了细胞存活的控制范围。在成熟B细胞中特异性地阻断典型的核因子-kappaB信号时，MZB细胞的分化和/或持久性仍然被取消，但滤泡B细胞的数量仅受到轻微的影响。然而，突变细胞在激活后表现出更高的周转率和功能缺陷，这表明规范的NF-kappa B信号有助于它们的长期持久性和功能适合性。
Although canonical NF-kappa B signaling is crucial to generate a normal mature B-cell compartment, its role in the persistence of resting mature B cells is controversial. To resolve this conflict, we ablated NF-kappa B essential modulator (NEMO) and I kappa B kinase 2 (IKK2), two essential mediators of the canonical pathway, either early on in B-cell development or specifically in mature B cells. Early ablation severely inhibited the generation of all mature B-cell subsets, but follicular B-cell numbers could be largely rescued by ectopic expression of B-cell lymphoma 2 (Bcl2), despite a persisting block at the transitional stage. Marginal zone (MZ) B and B1 cells were not rescued, indicating a possible role of canonical NF-kappa B signals beyond the control of cell survival in these subsets. When canonical NF-kappa B signaling was ablated specifically in mature B cells, the differentiation and/or persistence of MZ B cells was still abrogated, but follicular B-cell numbers were only mildly affected. However, the mutant cells exhibited increased turnover as well as functional deficiencies upon activation, suggesting that canonical NF-kappa B signals contribute to their long-term persistence and functional fitness.