Department of Immunology, Institute of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan.
Doctoral Program in Medical Science, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan.
J Immunol. 2024 Jun 1;212(11):1819-1828. doi: 10.4049/jimmunol.2300771.
NK cells are cytotoxic innate lymphocytes that play a critical role in antitumor immunity. NK cells recognize target cells by using a repertoire of activating NK receptors and exert the effector functions. Although the magnitude of activation signals through activating NK receptors controls NK cell function, it has not been fully understood how these activating signals are modulated in NK cells. In this study, we found that a scaffold protein, THEMIS2, inhibits activating NK receptor signaling. Overexpression of THEMIS2 attenuated the effector function of human NK cells, whereas knockdown of THEMIS2 enhanced it. Mechanistically, THEMIS2 binds to GRB2 and phosphorylated SHP-1 and SHP-2 at the proximity of activating NK receptors DNAM-1 and NKG2D. Knockdown of THEMIS2 in primary human NK cells promoted the effector functions. Furthermore, Themis2-deficient mice showed low metastatic burden in an NK cell-dependent manner. These findings demonstrate that THEMIS2 has an inhibitory role in the antitumor activity of NK cells, suggesting that THEMIS2 might be a potential therapeutic target for NK cell-mediated cancer immunotherapy.
自然杀伤 (NK) 细胞是细胞毒性先天淋巴细胞，在抗肿瘤免疫中发挥关键作用。NK 细胞通过一系列激活的 NK 受体识别靶细胞，并发挥效应功能。虽然通过激活的 NK 受体的激活信号的幅度控制 NK 细胞的功能，但尚未完全理解这些激活信号在 NK 细胞中如何被调节。在这项研究中，我们发现支架蛋白 THEMIS2 抑制激活的 NK 受体信号。THEMIS2 的过表达减弱了人 NK 细胞的效应功能，而 THEMIS2 的敲低则增强了它。在机制上，THEMIS2 与 GRB2 结合，并在激活的 NK 受体 DNAM-1 和 NKG2D 的附近使 SHP-1 和 SHP-2 磷酸化。在原代人 NK 细胞中敲低 THEMIS2 促进了效应功能。此外，Themis2 缺陷小鼠以 NK 细胞依赖性方式显示出较低的转移负担。这些发现表明 THEMIS2 在 NK 细胞的抗肿瘤活性中具有抑制作用，提示 THEMIS2 可能是 NK 细胞介导的癌症免疫治疗的潜在治疗靶点。
