IL4 and IL21 cooperate to induce the high Bcl6 protein level required for germinal center formation
IL4 and IL21 cooperate to induce the high Bcl6 protein level required for germinal center formation
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DOI：
10.1038/icb.2017.71
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发表时间：
2017-11-01
影响因子：
4
通讯作者：
Corcoran, Lynn M.
中科院分区：
文献类型：
--
作者：
Chevrier, Stephane;Kratina, Tobias;Corcoran, Lynn M.
Bcl6(B细胞淋巴瘤6)是一种转录抑制因子，也是T细胞依赖性抗体应答中生发中心反应的关键介质，通过抑制Blimp1使免疫球蛋白基因发生体细胞过度突变，抑制终末分化。当表达不当时，它也可能导致弥漫性大B细胞淋巴瘤的发展。Bcl6的调节是在转录和转录后水平上进行的，尤其是通过B细胞受体的强烈信号会导致Bcl6蛋白酶体的快速降解。尽管Bcl6在免疫和癌症中都很重要，但人们对其他外部因素如何调节B细胞中的Bcl6知之甚少。在这里，我们证明了Bcl6在B细胞受体(BCR)信号后确实在B细胞中高度不稳定，但T细胞衍生的细胞因子白介素4(IL4)和IL21抵消了BCR介导的降解，保持了Bcl6的蛋白水平。STAT6位于IL4下游，可直接诱导Bcl6转录。在体内，B细胞固有的IL4或IL21信号的缺失分别减少了GC反应的幅度或持续时间，而它们的联合丢失几乎完全消除了GC反应。这项工作对T滤泡辅助细胞因子在Bcl6调节中的作用提供了关键的见解。
Bcl6 (B-cell lymphoma 6) is a transcriptional repressor and critical mediator of the germinal center reaction during a T-cell-dependent antibody response, where it enables somatic hypermutation of immunoglobulin genes and inhibits terminal differentiation via repression of Blimp1. It can also contribute to the development of diffuse large B-cell lymphoma when expressed inappropriately. Bcl6 regulation is mediated both at the transcriptional and post-transcriptional levels, and in particular a strong signal through the B-cell receptor causes rapid proteasomal degradation of Bcl6. Despite the importance of Bcl6 in both immunity and cancer, little is known about how other extrinsic factors regulate Bcl6 in B cells. Here we show that Bcl6 is indeed highly unstable in B cells after a B-cell receptor (BCR) signal, but that the T-cell-derived cytokines interleukin 4 (IL4) and IL21 counteract BCR-mediated degradation, preserving Bcl6 protein levels. Stat6, downstream of IL4, can induce Bcl6 transcription directly. In vivo, B-cell intrinsic loss of IL4 or IL21 signaling reduces the magnitude or duration of the GC response, respectively, while their combined loss almost completely eliminates the GC response. This work provides key insights into the effect mediated by T-follicular helper cytokines on Bcl6 regulation.