Committee on Immunology, Department of Pathology, Howard Hughes Medical Institute, and Department of Chemistry, University of Chicago, Chicago, IL 60637Committee on Immunology, Department of Pathology, Howard Hughes Medical Institute, and Department of Chemistry, University of Chicago, Chicago, IL 60637Committee on Immunology, Department of Pathology, Howard Hughes Medical Institute, and Department of Chemistry, University of Chicago, Chicago, IL 60637.
Committee on Immunology, Department of Pathology, Howard Hughes Medical Institute, and Department of Chemistry, University of Chicago, Chicago, IL 60637Committee on Immunology, Department of Pathology, Howard Hughes Medical Institute, and Department of Chemistry, University of Chicago, Chicago, IL 60637.
J Exp Med. 2014 Jun 2;211(6):1137-51. doi: 10.1084/jem.20132267. Epub 2014 May 26.
Induction of Bcl6 (B cell lymphoma 6) is essential for T follicular helper (Tfh) cell differentiation of antigen-stimulated CD4(+) T cells. Intriguingly, we found that Bcl6 was also highly and transiently expressed during the CD4(+)CD8(+) (double positive [DP]) stage of T cell development, in association with the E3 ligase cullin 3 (Cul3), a novel binding partner of Bcl6 which ubiquitinates histone proteins. DP stage-specific deletion of the E3 ligase Cul3, or of Bcl6, induced the derepression of the Bcl6 target genes Batf (basic leucine zipper transcription factor, ATF-like) and Bcl6, in part through epigenetic modifications of CD4(+) single-positive thymocytes. Although they maintained an apparently normal phenotype after emigration, they expressed increased amounts of Batf and Bcl6 at basal state and produced explosive and prolonged Tfh responses upon subsequent antigen encounter. Ablation of Cul3 in mature CD4(+) splenocytes also resulted in dramatically exaggerated Tfh responses. Thus, although previous studies have emphasized the essential role of Bcl6 in inducing Tfh responses, our findings reveal that Bcl6-Cul3 complexes also provide essential negative feedback regulation during both thymocyte development and T cell activation to restrain excessive Tfh responses.
Bcl6（B 细胞淋巴瘤 6）的诱导对于抗原刺激的 CD4+T 细胞中滤泡辅助性 T 细胞（Tfh）的分化是必不可少的。有趣的是，我们发现 Bcl6 在 T 细胞发育的 CD4+CD8+（双阳性[DP]）阶段也高度且短暂地表达，与 E3 连接酶 Cullin 3（Cul3）有关，Cul3 是 Bcl6 的一种新型结合伴侣，可泛素化组蛋白蛋白。DP 阶段特异性删除 E3 连接酶 Cul3 或 Bcl6 会诱导 Bcl6 靶基因 Batf（碱性亮氨酸拉链转录因子，ATF 样）和 Bcl6 的去抑制，部分通过 CD4+单阳性胸腺细胞的表观遗传修饰。尽管它们在迁出后仍保持明显正常的表型，但在随后遇到抗原时，它们在基础状态下表达更多的 Batf 和 Bcl6，并产生爆发性和延长的 Tfh 反应。成熟 CD4+脾细胞中 Cul3 的缺失也导致 Tfh 反应显著增强。因此，尽管先前的研究强调了 Bcl6 在诱导 Tfh 反应中的重要作用，但我们的发现表明 Bcl6-Cul3 复合物在胸腺细胞发育和 T 细胞激活期间也提供了必需的负反馈调节，以抑制过度的 Tfh 反应。
