Journal
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
Volume 142, Issue 4, Pages 1311-+Publisher
MOSBY-ELSEVIER
DOI: 10.1016/j.jaci.2018.02.050
Keywords
Natural killer cell; programmed cell death protein 1; lytic granule; leukocyte function-associated antigen 1; immunological synapse
Categories
Funding
- Houston Methodist Career Cornerstone Award
- Lymphoma SPORE Developmental Research Program [P50 CA126752]
- Houston Methodist Research Institute for Academic Medicine NIH Competitiveness Initiative Award
- Baylor-UT Houston Center for AIDS Research Core Support grant from the National Institute of Allergy and Infectious Diseases [AI036211]
- [HL125018]
- [AI124769]
- [AI129594]
- [AI130197]
- [R01 NS102452]
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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 cytotox`icity 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.
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