Abstract
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.
Original language | English (US) |
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Pages (from-to) | 1311-1321.e8 |
Journal | Journal of Allergy and Clinical Immunology |
Volume | 142 |
Issue number | 4 |
DOIs | |
State | Published - Oct 2018 |
Keywords
- Natural killer cell
- immunological synapse
- leukocyte function–associated antigen 1
- lytic granule
- programmed cell death protein 1
ASJC Scopus subject areas
- Immunology and Allergy
- Immunology