免疫突触
NKG2D公司
细胞生物学
自然杀伤细胞
CD16
溶解循环
CD49b
颗粒酶B
生物
淋巴因子激活杀伤细胞
颗粒酶
信号转导
细胞毒性
白细胞介素21
免疫系统
免疫学
CD8型
T细胞
CD3型
穿孔素
T细胞受体
病毒
生物化学
体外
作者
Yhu‐Chering Huang,Zhiying Chen,Joon Hee Jang,Mirza S. Baig,Grant Bertolet,Casey L. C. Schroeder,Shouying Huang,Qian Hu,Yong Zhao,Dorothy E. Lewis,Lidong Qin,Michael X. Zhu,Dongfang Liu
标识
DOI:10.1016/j.jaci.2018.02.050
摘要
The inhibitory receptor programmed cell death protein 1 (PD-1) is upregulated on a variety of immune cells, including natural killer (NK) cells, during chronic viral infection and tumorigenesis. Blockade of PD-1 or its ligands produces durable clinical responses with tolerable side effects in patients with a broad spectrum of cancers. However, the underlying molecular mechanisms of how PD-1 regulates NK cell function remain poorly characterized.We sought to determine the effect of PD-1 signaling on NK cells.PD-1 was overexpressed in CD16-KHYG-1 (a human NK cell line with both antibody-dependent cellular cytotoxicity through CD16 and natural cytotoxicity through NKG2D) cells and stimulated by exposing the cells to NK-sensitive target cells expressing programmed death ligand 1 (PD-L1).PD-1 engagement by PD-L1 specifically blocked NK cell-mediated cytotoxicity without interfering with the conjugation between NK cells and target cells. Further examination showed that PD-1 signaling blocked lytic granule polarization in NK cells, which was accompanied by failure of integrin-linked kinase, a key molecule in the integrin outside-in signaling pathway, to accumulate in the immunological synapse after NK-target cell conjugation.Our results suggest that NK cell cytotoxicity is inhibited by PD-1 engagement, which blocks lytic granule polarization to the NK cell immunological synapse with concomitant impairment of integrin outside-in signaling. This study provides novel mechanistic insights into how PD-1 inhibition disrupts NK cell function.
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