Faculty of Biology, University of Freiburg, Freiburg, Germany.
Signaling Research Centers BIOSS and CIBSS, University of Freiburg, Freiburg, Germany.
Cell Mol Life Sci. 2021 Dec;78(24):8165-8186. doi: 10.1007/s00018-021-04009-z. Epub 2021 Nov 3.
B cell superantigens crosslink conserved domains of B cell receptors (BCRs) and cause dysregulated, polyclonal B cell activation irrespective of normal BCR-antigen complementarity. The cells typically succumb to activation-induced cell death, which can impede the adaptive immune response and favor infection. In the present study, we demonstrate that the fucose-binding lectin of Burkholderia ambifaria, BambL, bears functional resemblance to B cell superantigens. By engaging surface glycans, the bacterial lectin activated human peripheral blood B cells, which manifested in the surface expression of CD69, CD54 and CD86 but became increasingly cytotoxic at higher concentrations. The effects were sensitive to BCR pathway inhibitors and excess fucose, which corroborates a glycan-driven mode of action. Interactome analyses in a model cell line suggest BambL binds directly to glycans of the BCR and regulatory coreceptors. In vitro, BambL triggered BCR signaling and induced CD19 internalization and degradation. Owing to the lectin's six binding sites, we propose a BCR activation model in which BambL functions as a clustering hub for receptor glycans, modulates normal BCR regulation, and induces cell death through exhaustive activation.
B 细胞超抗原交联 B 细胞受体 (BCR) 的保守结构域，导致不受正常 BCR-抗原互补性调节的多克隆 B 细胞激活。这些细胞通常会因激活诱导的细胞死亡而死亡，这可能会阻碍适应性免疫反应并有利于感染。在本研究中，我们证明了伯克霍尔德菌 ambifaria 的岩藻糖结合凝集素 BambL 具有与 B 细胞超抗原相似的功能。通过与表面糖结合，细菌凝集素激活了人外周血 B 细胞，这表现在 CD69、CD54 和 CD86 的表面表达上，但在更高浓度下细胞毒性逐渐增加。这些效应对 BCR 途径抑制剂和过量岩藻糖敏感，这证实了一种糖驱动的作用模式。在模型细胞系中的相互作用分析表明 BambL 直接结合 BCR 和调节性共受体的糖链。在体外，BambL 触发了 BCR 信号转导，并诱导了 CD19 的内化和降解。由于凝集素有六个结合位点，我们提出了一个 BCR 激活模型，其中 BambL 作为受体糖链的聚集中心发挥作用，调节正常的 BCR 调节，并通过过度激活诱导细胞死亡。
