Department of Microbiology, Immunology and Infectious Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta T2N 4N1, Canada.
Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta T2N 4N1, Canada; and.
J Immunol. 2018 Oct 15;201(8):2369-2376. doi: 10.4049/jimmunol.1701805. Epub 2018 Sep 10.
is a fungal pathogen that causes fatal meningitis and pneumonia. During host defense to , NK cells directly recognize and kill using cytolytic degranulation analogous to killing of tumor cells. This fungal killing requires independent activation of Src family kinase (SFK) and Rac1-mediated pathways. Recognition of requires the natural cytotoxicity receptor, NKp30; however, it is not known whether NKp30 activates both signal transduction pathways or whether a second receptor is involved in activation of one of the pathways. We used primary human NK cells and a human NK cell line and found that NKp30 activates SFK → PI3K but not Rac1 cytotoxic signaling, which led to a search for the receptor leading to Rac1 activation. We found that NK cells require integrin-linked kinase (ILK) to activate Rac1 for effective fungal killing. This observation led to our identification of β1 integrin as an essential anticryptococcal receptor. These findings demonstrate that multiple receptors, including β1 integrins and NKp30 and their proximal signaling pathways, are required for recognition of , which activates a central cytolytic antimicrobial pathway leading to fungal killing.
是一种真菌病原体，可导致致命的脑膜炎和肺炎。在宿主防御过程中，NK 细胞通过类似于杀伤肿瘤细胞的细胞溶解脱粒直接识别和杀死。这种真菌杀伤需要独立激活Src 家族激酶（SFK）和 Rac1 介导的途径。识别需要自然细胞毒性受体 NKp30；然而，尚不清楚 NKp30 是否激活这两条信号转导途径，或者是否有第二个受体参与其中一条途径的激活。我们使用原代人 NK 细胞和人 NK 细胞系发现，NKp30 激活 SFK→PI3K，但不激活 Rac1 细胞毒性信号，这促使我们寻找导致 Rac1 激活的受体。我们发现 NK 细胞需要整合素连接激酶（ILK）来激活 Rac1 以有效杀伤真菌。这一观察结果导致我们鉴定出β1 整合素是一种必需的抗隐球菌受体。这些发现表明，包括β1 整合素和 NKp30 及其近端信号通路在内的多种受体，对于识别至关重要，这激活了一种导致真菌杀伤的中央细胞溶解抗菌途径。
