SARS-CoV-2 infection impairs NK cell functions via activation of the LLT1-CD161 axis.

Autor:	Lenart M; Virogenetics Laboratory of Virology, Malopolska Centre of Biotechnology, Jagiellonian University, Krakow, Poland., Górecka M; Virogenetics Laboratory of Virology, Malopolska Centre of Biotechnology, Jagiellonian University, Krakow, Poland., Bochenek M; Flow Cytometry Core Facility, Malopolska Centre of Biotechnology, Jagiellonian University, Krakow, Poland., Barreto-Duran E; Virogenetics Laboratory of Virology, Malopolska Centre of Biotechnology, Jagiellonian University, Krakow, Poland., Szczepański A; Virogenetics Laboratory of Virology, Malopolska Centre of Biotechnology, Jagiellonian University, Krakow, Poland., Gałuszka-Bulaga A; Department of Clinical Immunology, Institute of Pediatrics, Jagiellonian University Medical College, Krakow, Poland., Mazur-Panasiuk N; Virogenetics Laboratory of Virology, Malopolska Centre of Biotechnology, Jagiellonian University, Krakow, Poland., Węglarczyk K; Department of Clinical Immunology, Institute of Pediatrics, Jagiellonian University Medical College, Krakow, Poland., Siwiec-Koźlik A; Department of Rheumatology and Immunology, Jagiellonian University Medical College, Krakow, Poland.; 2nd Department of Internal Medicine, University Hospital, Krakow, Poland., Korkosz M; Department of Rheumatology and Immunology, Jagiellonian University Medical College, Krakow, Poland., Łabaj PP; Bioinformatics Research Group, Malopolska Centre of Biotechnology, Jagiellonian University, Krakow, Poland., Baj-Krzyworzeka M; Department of Clinical Immunology, Institute of Pediatrics, Jagiellonian University Medical College, Krakow, Poland., Siedlar M; Department of Clinical Immunology, Institute of Pediatrics, Jagiellonian University Medical College, Krakow, Poland., Pyrc K; Virogenetics Laboratory of Virology, Malopolska Centre of Biotechnology, Jagiellonian University, Krakow, Poland.
Jazyk:	angličtina
Zdroj:	Frontiers in immunology [Front Immunol] 2023 May 23; Vol. 14, pp. 1123155. Date of Electronic Publication: 2023 May 23 (Print Publication: 2023).
DOI:	10.3389/fimmu.2023.1123155
Abstrakt:	Introduction: Natural killer (NK) cells plays a pivotal role in the control of viral infections, and their function depend on the balance between their activating and inhibitory receptors. The immune dysregulation observed in COVID-19 patients was previously associated with downregulation of NK cell numbers and function, yet the mechanism of inhibition of NK cell functions and the interplay between infected cells and NK cells remain largely unknown. Methods: In this study we show that SARS-CoV-2 infection of airway epithelial cells can directly influence NK cell phenotype and functions in the infection microenvironment. NK cells were co-cultured with SARS-CoV-2 infected epithelial cells, in a direct contact with A549 ACE2/TMPRSS2 cell line or in a microenvironment of the infection in a 3D ex vivo human airway epithelium (HAE) model and NK cell surface expression of a set of most important receptors (CD16, NKG2D, NKp46, DNAM-1, NKG2C, CD161, NKG2A, TIM-3, TIGIT, and PD-1) was analyzed. Results: We observed a selective, in both utilized experimental models, significant downregulation the proportion of CD161 (NKR-P1A or KLRB1) expressing NK cells, and its expression level, which was followed by a significant impairment of NK cells cytotoxicity level against K562 cells. What is more, we confirmed that SARS-CoV-2 infection upregulates the expression of the ligand for CD161 receptor, lectin-like transcript 1 (LLT1, CLEC2D or OCIL), on infected epithelial cells. LLT1 protein can be also detected not only in supernatants of SARS-CoV-2 infected A549 ACE2/TMPRSS2 cells and HAE basolateral medium, but also in serum of COVID-19 patients. Finally, we proved that soluble LLT1 protein treatment of NK cells significantly reduces i) the proportion of CD161+ NK cells, ii) the ability of NK cells to control SARS-CoV-2 infection in A549 ACE2/TMPRSS2 cells and iii) the production of granzyme B by NK cells and their cytotoxicity capacity, yet not degranulation level. Conclusion: We propose a novel mechanism of SARS-CoV-2 inhibition of NK cell functions via activation of the LLT1-CD161 axis. Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2023 Lenart, Górecka, Bochenek, Barreto-Duran, Szczepański, Gałuszka-Bulaga, Mazur-Panasiuk, Węglarczyk, Siwiec-Koźlik, Korkosz, Łabaj, Baj-Krzyworzeka, Siedlar and Pyrc.)
Databáze:	MEDLINE
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