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Defining the role of natural killer cells in COVID-19

Nature Immunology volume 24, pages 1628–1638 (2023)Cite this article

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Abstract

Natural killer (NK) cells are critical effectors of antiviral immunity. Researchers have therefore sought to characterize the NK cell response to coronavirus disease 2019 (COVID-19) and the virus that causes it, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The NK cells of patients with severe COVID-19 undergo extensive phenotypic and functional changes. For example, the NK cells from critically ill patients with COVID-19 are highly activated and exhausted, with poor cytotoxic function and cytokine production upon stimulation. The NK cell response to SARS-CoV-2 is also modulated by changes induced in virally infected cells, including the ability of a viral peptide to bind HLA-E, preventing NK cells from receiving inhibitory signals, and the downregulation of major histocompatibility complex class I and ligands for the activating receptor NKG2D. These changes have important implications for the ability of infected cells to escape NK cell killing. The implications of these findings for antibody-dependent NK cell activity in COVID-19 are also reviewed. Despite these advances in the understanding of the NK cell response to SARS-CoV-2, there remain critical gaps in our current understanding and a wealth of avenues for future research on this topic.

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Fig. 1: Changes in NK cell phenotype induced by severe COVID-19.
Fig. 2: Mechanisms underlying NK cell activation, exhaustion and dysfunction in severe COVID-19.
Fig. 3: Mechanisms of ligand modulation by SARS-CoV-2 in infected cells.
Fig. 4: The two-pronged escape of NK cell killing by SARS-CoV-2.

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Acknowledgements

Funding for C.A.B. was provided by the Burroughs Wellcome Fund, 1016687; the National Institute of Allergy and Infectious Diseases (NIAID), U19AI057229; the Bill and Melinda Gates Foundation, OPP1113682; and the Chan Zuckerberg Biohub Investigator Award. Funding for M.J.L. was provided by the National Institute of Allergy and Infectious Diseases (NIAID), 1F31AI172319-01.

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Authors and Affiliations

  1. Stanford Immunology Program, Stanford University School of Medicine, Stanford, CA, USA

    Madeline J. Lee

  2. Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA

    Madeline J. Lee & Catherine A. Blish

  3. Chan Zuckerberg Biohub, San Francisco, CA, USA

    Catherine A. Blish

  4. Stanford Medical Scientist Training Program, Stanford University School of Medicine, Stanford, CA, USA

    Catherine A. Blish

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  1. Madeline J. Lee
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M.J.L. and C.A.B. conceived and wrote the manuscript.

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Correspondence to Catherine A. Blish.

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Competing interests

C.A.B. reports compensation for consulting and/or SAB membership from Catamaran Bio, DeepCell, Immunebridge, Sangamo Therapeutics and Bicycle Tx on topics unrelated to this review. M.J.L. declares no competing interests.

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Nature Immunology thanks Timothy O’Sullivan and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: L. A. Dempsey, in collaboration with the Nature Immunology team.

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Lee, M.J., Blish, C.A. Defining the role of natural killer cells in COVID-19. Nat Immunol 24, 1628–1638 (2023). https://doi.org/10.1038/s41590-023-01560-8

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