Li Shu Shun, Ogbomo Henry, Mansour Michael K, Xiang Richard F, Szabo Lian, Munro Fay, Mukherjee Priyanka, Mariuzza Roy A, Amrein Matthias, Vyas Jatin M, Robbins Stephen M, Mody Christopher H
Department of Microbiology, Immunology and Infectious Diseases, University of Calgary, Calgary, T2N 4N1, Canada.
The Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, T2N 4N1, Canada.
Nat Commun. 2018 Feb 21;9(1):751. doi: 10.1038/s41467-018-03014-4.
Natural killer (NK) cells use the activating receptor NKp30 as a microbial pattern-recognition receptor to recognize, activate cytolytic pathways, and directly kill the fungi Cryptococcus neoformans and Candida albicans. However, the fungal pathogen-associated molecular pattern (PAMP) that triggers NKp30-mediated killing remains to be identified. Here we show that β-1,3-glucan, a component of the fungal cell wall, binds to NKp30. We further demonstrate that β-1,3-glucan stimulates granule convergence and polarization, as shown by live cell imaging. Through Src Family Kinase signaling, β-1,3-glucan increases expression and clustering of NKp30 at the microbial and NK cell synapse to induce perforin release for fungal cytotoxicity. Rather than blocking the interaction between fungi and NK cells, soluble β-1,3-glucan enhances fungal killing and restores defective cryptococcal killing by NK cells from HIV-positive individuals, implicating β-1,3-glucan to be both an activating ligand and a soluble PAMP that shapes NK cell host immunity.
自然杀伤（NK）细胞利用激活受体NKp30作为微生物模式识别受体来识别、激活溶细胞途径，并直接杀死新型隐球菌和白色念珠菌等真菌。然而，触发NKp30介导杀伤作用的真菌病原体相关分子模式（PAMP）仍有待确定。在此我们表明，真菌细胞壁的成分β-1,3-葡聚糖可与NKp30结合。我们进一步证明，如活细胞成像所示，β-1,3-葡聚糖可刺激颗粒聚集和极化。通过Src家族激酶信号传导，β-1,3-葡聚糖可增加NKp30在微生物与NK细胞突触处的表达和聚集，从而诱导穿孔素释放以实现对真菌的细胞毒性作用。可溶性β-1,3-葡聚糖并非阻断真菌与NK细胞之间的相互作用，而是增强真菌杀伤作用，并恢复HIV阳性个体的NK细胞对隐球菌杀伤缺陷，这表明β-1,3-葡聚糖既是一种激活配体，也是一种塑造NK细胞宿主免疫的可溶性PAMP。
