B Cell Receptor-Mediated Sustained c-Rel Activation Facilitates Late Transitional B Cell Survival through Control of B Cell Activating Factor Receptor and NF-κB21-猫眼课题宝

B 细胞受体介导的持续 c-Rel 激活通过控制 B 细胞激活因子受体和 NF-κB21 促进晚期过渡 B 细胞存活

DOI：

发表时间：

2009

期刊：

Journal of Immunology

影响因子：

4.4

通讯作者：

中科院分区：

医学2区

文献类型：

作者：

I. Castro;Jacqueline A. Wright;B. Damdinsuren;K. Hoek;G. Carlesso;N. Shinners;R. Gerstein;R. T. Woodland;R. Sen;W. Khan

在产生成熟 B 淋巴细胞的选择过程中，来自 BCR 和 B 细胞激活因子受体（BAFF-R 或 BR3）的信号传导差异性地调节早期过渡 (T1) 和晚期过渡 (T2；CD21int-T2) B 细胞的凋亡。然而，移行 B 细胞对细胞凋亡差异敏感性的分子机制仍不清楚。在这项研究中，我们证明 BCR 信号传导在 T2 和成熟 B 细胞中诱导比 T1 B 细胞更长期的 c-Rel 激活，导致抗凋亡基因以及促存活 BAFF-R 及其下游底物 p100 (NF-κB2) 的表达增加。持续的 c-Rel 激活需要通过 Btk 依赖性机制从头开始 c-Rel 基因转录和翻译。与 T1 细胞一样，来自 Btk 和 c-Rel 缺陷小鼠的成熟 B 细胞也无法激活这些基因。这些发现表明，过渡型 B 细胞内生存潜力的获得取决于产生长期 c-Rel 反应的能力，该反应通过诱导抗凋亡基因 BAFF-R 和 NF-κB2（BAFF-R 生存信号传导的重要组成部分）在体内 T2 B 细胞存活和分化中发挥关键作用。因此，在过渡性 B 细胞成熟过程中获得对细胞凋亡的抵抗是通过 BCR 和 BAFF-R 信号的整合来实现的。

Signaling from the BCR and B cell activating factor receptor (BAFF-R or BR3) differentially regulates apoptosis within early transitional (T1) and late transitional (T2; CD21int-T2) B cells during selection processes to generate mature B lymphocytes. However, molecular mechanisms underlying the differential sensitivity of transitional B cells to apoptosis remain unclear. In this study, we demonstrate that BCR signaling induced more long-term c-Rel activation in T2 and mature than in T1 B cells leading to increased expression of anti-apoptotic genes as well as prosurvival BAFF-R and its downstream substrate p100 (NF-κB2). Sustained c-Rel activation required de novo c-Rel gene transcription and translation via Btk-dependent mechanisms. Like T1 cells, mature B cells from Btk- and c-Rel-deficient mice also failed to activate these genes. These findings suggest that the gain of survival potential within transitional B cells is dependent on the ability to produce a long-term c-Rel response, which plays a critical role in T2 B cell survival and differentiation in vivo by inducing anti-apoptotic genes, BAFF-R and NF-κB2, an essential component for BAFF-R survival signaling. Thus, acquisition of resistance to apoptosis during transitional B cell maturation is achieved by integration of BCR and BAFF-R signals.