B Cell Receptor-Mediated Sustained c-Rel Activation Facilitates Late Transitional B Cell Survival through Control of B Cell Activating Factor Receptor and NF-κB2
B Cell Receptor-Mediated Sustained c-Rel Activation Facilitates Late Transitional B Cell Survival through Control of B Cell Activating Factor Receptor and NF-κB2
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DOI：
10.4049/jimmunol.0803281
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发表时间：
2009-06-15
影响因子：
4.4
通讯作者：
Khan, Wasif N.
中科院分区：
文献类型：
--
作者：
Castro, Iris;Wright, Jacqueline A.;Khan, Wasif N.
来自BCR抗B细胞激活因子受体(BAFF-R或BR3)的信号在选择过程中差异地调节早期过渡(T1)和晚期过渡(T2；CD21(Int)-T2)B细胞的凋亡，以产生成熟的B淋巴细胞。然而，过渡性B细胞对凋亡的不同敏感性的分子机制仍不清楚。在这项研究中，我们证明了BC-R信号在T2抗成熟细胞中比在T1 B细胞中诱导了更多的长期c-rel激活，导致了抗凋亡基因的表达增加，以及BAFF-R及其下游底物P100(NF-kappa B2)的存活。持续的c-rel激活需要通过依赖BTK的机制重新转录和翻译c-rel基因。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，过渡性13细胞内生存潜力的增加依赖于产生长期c-rel反应的能力，c-rel反应通过诱导抗凋亡基因BAFF-R和BAFF-R生存信号的重要组成部分--核因子-kappa B2，在体内对T2 B细胞的生存和分化起关键作用。因此，通过整合BCR和BAFF-R信号，在过渡性B细胞成熟过程中获得了对凋亡的抵抗。免疫学杂志，2009,182：7729-7737。
Signaling from the BCR anti B cell activating factor receptor (BAFF-R or BR3) differentially regulates apoptosis within early transitional (T1) and late transitional (T2; CD21(int)-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 BC R signaling induced more long-term c-Rel activation in T2 anti 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-kappa B2). 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 13 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-kappa B2, 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. The Journal of Immunology, 2009, 182: 7729-7737.