B细胞补体信号的动态调节对于生发中心反应是必需的
2021-06-06   阅读:349   来源:自然

美国西奈山伊坎医学院Peter S. Heeger、David Dominguez-Sola等研究人员合作发现,B细胞补体信号的动态调节对于生发中心反应是必需的。该项研究成果于2021年5月24日在线发表在《自然—免疫学》杂志上。

研究人员表示,生发中心(GC)内B细胞的成熟会产生多样化的B细胞库和高亲和力的B细胞抗原受体(BCR),从而清除病原体。通过T细胞依赖的、基于亲和力的B细胞正向选择以及克隆扩增的反复循环可以提高受体的亲和力,但背后的机制仍不明确。

研究人员发现,作为生理程序的一部分,GC B细胞通过BCL6抑制了衰退加速因子(DAF/CD55)和其他补体C3转化酶调节因子的表达,但增加了C5b-9抑制因子CD59的表达。这些变化使得C3在GC B细胞表面切割,而不会形成膜攻击复合物和正向选择所需的活化型C3a和C5a受体信号。条件性转基因DAF的过表达或C3a和C5a受体的缺失导致抗原激活B细胞途径的遗传破坏,限制了mTOR(mechanistic target of rapamycin)对BCR–CD40信号的响应,并导致过早的GC崩溃和亲和力成熟受损。这些结果表明,GC内补体调节的协调性转变为GC B细胞的正向选择提供了关键信号。

附:英文原文

Title: Dynamic regulation of B cell complement signaling is integral to germinal center responses

Author: Arun Cumpelik, David Heja, Yuan Hu, Gabriele Varano, Farideh Ordikhani, Mark P. Roberto, Zhengxiang He, Dirk Homann, Sergio A. Lira, David Dominguez-Sola, Peter S. Heeger

Issue&Volume: 2021-05-24

Abstract: Maturation of Bcells within germinal centers (GCs) generates diversified B cell pools and high-affinity B cell antigen receptors (BCRs) for pathogen clearance. Increased receptor affinity is achieved by iterative cycles of T cell–dependent, affinity-based B cell positive selection and clonal expansion by mechanisms hitherto incompletely understood. Here we found that, as part of a physiologic program, GC Bcells repressed expression of decay-accelerating factor (DAF/CD55) and other complement C3 convertase regulators via BCL6, but increased the expression of C5b-9 inhibitor CD59. These changes permitted C3 cleavage on GC B cell surfaces without the formation of membrane attack complex and activated C3a- and C5a-receptor signals required for positive selection. Genetic disruption of this pathway in antigen-activated Bcells by conditional transgenic DAF overexpression or deletion of C3a and C5a receptors limited the activation of mechanistic target of rapamycin (mTOR) in response to BCR–CD40 signaling, causing premature GC collapse and impaired affinity maturation. These results reveal that coordinated shifts in complement regulation within the GC provide crucial signals underlying GC B cell positive selection.

DOI: 10.1038/s41590-021-00926-0

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