B cell maturation depends on cognate interactions between the T and B cells. Upon interaction with CD40 ligand (CD40L) on T cells, CD40 delivers costimulatory signals alongside B cell antigen receptor (BCR) signaling to regulate affinity maturation and antibody class switch. Mutations affecting CD40-CD40L interactions cause abnormal antibody responses in immunodeficiencies known as X-linked hyper-IgM syndrome (X-HIgM). Here, we study the CD40-mediated mechanotransduction in B cells, which likely occurs during their physical contacts with T cells. We found that CD40 forms catch bond with CD40L that lasts longer at larger forces, both B and T cells exert tension on CD40-CD40L bonds, and force enhances CD40 signaling and antibody class switch. X-HIgM CD40L mutations impair catch bond formation, suppress endogenous tension, and reduce force-enhanced CD40 signaling, leading to deficiencies in antibody class switch. Our findings highlight the role of mechanotransduction in CD40 function and provide insights into the mechanisms underlying X-HIgM syndrome.

中文翻译：

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机械转导控制 CD40 功能，是 X 连锁高 IgM 综合征的基础


B 细胞成熟取决于 T 细胞和 B 细胞之间的同源相互作用。与 T 细胞上的 CD40 配体 （CD40L） 相互作用后，CD40 与 B 细胞抗原受体 （BCR） 信号传导一起传递共刺激信号，以调节亲和力成熟和抗体类别转换。影响 CD40-CD40L 相互作用的突变会导致免疫缺陷中的抗体反应异常，称为 X 连锁高 IgM 综合征 （X-HIgM）。在这里，我们研究了 B 细胞中 CD40 介导的机械转导，这可能发生在它们与 T 细胞的物理接触期间。我们发现 CD40 与 CD40L 形成捕获键，在较大的力下持续时间更长，B 细胞和 T 细胞都对 CD40-CD40L 键施加张力，力增强 CD40 信号传导和抗体类别转换。X-HIgM CD40L 突变会损害捕获键的形成，抑制内源性张力，并减少力增强的 CD40 信号传导，从而导致抗体类别转换的缺陷。我们的研究结果强调了机械转导在 CD40 功能中的作用，并为 X-HIgM 综合征的潜在机制提供了见解。