Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143.
Parker Institute for Cancer Immunotherapy, San Francisco, CA 94143.
J Immunol. 2018 May 15;200(10):3420-3428. doi: 10.4049/jimmunol.1701639. Epub 2018 Apr 4.
Natural killer cells are critical in the immune response to infection and malignancy. Prior studies have demonstrated that Crk family proteins can influence cell apoptosis, proliferation, and cell transformation. In this study, we investigated the role of Crk family proteins in mouse NK cell differentiation and host defense using a mouse CMV infection model. The number of NK cells, maturational state, and the majority of the NKR repertoire was similar in Crk x Crk-like (CrkL)-double-deficient and wild type NK cells. However, Crk family proteins were required for optimal activation, IFN-γ production, expansion, and differentiation of Ly49H NK cells, as well as host defense during mouse CMV infection. The diminished function of Crk x CrkL-double-deficient NK cells correlated with decreased phosphorylation of STAT4 and STAT1 in response to IL-12 and IFN-α stimulation, respectively. Together, our findings analyzing NK cell-specific Crk-deficient mice provide insights into the role of Crk family proteins in NK cell function and host defense.
自然杀伤细胞在感染和恶性肿瘤的免疫反应中至关重要。先前的研究表明，Crk 家族蛋白可以影响细胞凋亡、增殖和细胞转化。在这项研究中，我们使用小鼠 CMV 感染模型研究了 Crk 家族蛋白在小鼠 NK 细胞分化和宿主防御中的作用。在 Crk x Crk 样（CrkL）双缺失和野生型 NK 细胞中，NK 细胞的数量、成熟状态和大多数 NKR 库相似。然而，Crk 家族蛋白对于 Ly49H NK 细胞的最佳激活、IFN-γ 产生、扩增和分化以及小鼠 CMV 感染期间的宿主防御是必需的。Crk x CrkL 双缺失 NK 细胞功能降低与 IL-12 和 IFN-α刺激后 STAT4 和 STAT1 的磷酸化减少相关。总之，我们对 NK 细胞特异性 Crk 缺失小鼠的分析结果提供了对 Crk 家族蛋白在 NK 细胞功能和宿主防御中的作用的深入了解。
