PD-1 blocks lytic granule polarization with concomitant impairment of integrin outside-in signaling in the natural killer cell immunological synapse

Publication date: October 2018

Source: Journal of Allergy and Clinical Immunology, Volume 142, Issue 4

Author(s): Yu Huang, Zhiying Chen, Joon Hee Jang, Mirza S. Baig, Grant Bertolet, Casey Schroeder, Shengjian Huang, Qian Hu, Yong Zhao, Dorothy E. Lewis, Lidong Qin, Michael Xi Zhu, Dongfang Liu

Background

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.

Objective

We sought to determine the effect of PD-1 signaling on NK cells.

Methods

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).

Results

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.

Conclusion

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.

Graphical abstract

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