Glycobiology Research and Training Center, School of Medicine, University of California, San Diego, La Jolla, CA 92093.
Department of Cellular and Molecular Medicine, School of Medicine, University of California, San Diego, La Jolla, CA 92093.
Proc Natl Acad Sci U S A. 2018 Oct 9;115(41):10410-10415. doi: 10.1073/pnas.1804108115. Epub 2018 Sep 25.
Natural killer (NK) cells are innate immune lymphocytes that recognize and destroy abnormal host cells, such as tumor cells or those infected by viral pathogens. To safely accomplish these functions, NK cells display activating receptors that detect stress molecules or viral ligands displayed at the cell surface, balanced by inhibitory receptors that bind to self-molecules. To date, such activating and inhibitory receptors on NK cells are not known to recognize bacterial determinants. Moreover, NK cell responses to direct interactions with extracellular bacteria are poorly explored. In this study, we observed the human neonatal pathogen group B (GBS) can directly engage human NK cells. The interaction was mediated through the B6N segment of streptococcal β-protein, binding to the inhibitory receptor Siglec-7 via its amino-terminal V-set domain. Unlike classical Siglec binding, the interaction is also independent of its sialic acid recognition property. In contrast to WT GBS, mutants lacking β-protein induced efficient pyroptosis of NK cells through the NLRP3 inflammasome, with production and secretion of the proinflammatory cytokine IL-1β and dissemination of the cytotoxic molecule granzyme B. We postulate that GBS evolved β-protein engagement of inhibitory human Siglec-7 to suppress the pyroptotic response of NK cells and thereby block recruitment of a broader innate immune response, i.e., by "silencing the sentinel."
自然杀伤 (NK) 细胞是先天免疫淋巴细胞，可识别和破坏异常宿主细胞，如肿瘤细胞或受病毒病原体感染的细胞。为了安全地完成这些功能，NK 细胞表达激活受体，可识别细胞表面上显示的应激分子或病毒配体，同时平衡表达抑制受体，后者与自身分子结合。迄今为止，NK 细胞上的这些激活和抑制受体尚未被发现可识别细菌决定簇。此外，NK 细胞对与细胞外细菌直接相互作用的反应尚未得到充分探索。在这项研究中，我们观察到人类新生病原体 B 群（GBS）可直接与人类 NK 细胞相互作用。这种相互作用是通过链球菌β蛋白的 B6N 片段介导的，该片段通过其氨基末端 V 集结构域与抑制性受体 Siglec-7 结合。与经典 Siglec 结合不同，该相互作用也不依赖于其唾液酸识别特性。与 WT GBS 相反，缺乏 β 蛋白的突变体通过 NLRP3 炎性体诱导 NK 细胞有效的细胞焦亡，导致促炎细胞因子 IL-1β 的产生和分泌以及细胞毒性分子颗粒酶 B 的扩散。我们假设 GBS 进化出 β 蛋白与人类抑制性 Siglec-7 的结合，以抑制 NK 细胞的细胞焦亡反应，从而阻止更广泛的先天免疫反应的募集，即通过“沉默哨兵”。
