PD-1 blocks lytic granule polarization with concomitant impairment of integrin outside-in signaling in the natural killer cell immunological synapse - 05/10/18
, Dongfang Liu, PhD b, j, ⁎ 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.
Le texte complet de cet article est disponible en PDF.Graphical abstract |
Key words : Natural killer cell, programmed cell death protein 1, lytic granule, leukocyte function–associated antigen 1, immunological synapse
Abbreviations used : ADCC, GFP, ICAM-1, ILK, IS, LFA-1, LG, NK, NC, PD-1, PD-L1, TCR
Plan
| Supported in part by grants HL125018, AI124769, AI129594, and AI130197 (to D.L.); R01 NS102452 (to M.X.Z.); the Houston Methodist Career Cornerstone Award; the Lymphoma SPORE Developmental Research Program (P50 CA126752); Houston Methodist Research Institute for Academic Medicine NIH Competitiveness Initiative Award; and Baylor-UT Houston Center for AIDS Research Core Support grant number AI036211 from the National Institute of Allergy and Infectious Diseases. |
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| Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest. |
Vol 142 - N° 4
P. 1311 - octobre 2018 Retour au numéro
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