Interferon-mediated NK cell activation increases cytolytic activity against T follicular helper cells and limits antibody response to SARS-CoV-2

Izumi de Los Rios Kobara; Radeesha Jayewickreme; Madeline J Lee; Aaron J Wilk; Stanford COVID-19 Biobank; Andra L Blomkalns; Kari C Nadeau; Samuel Yang; Angela J Rogers; Catherine A Blish

doi:10.1038/s41590-025-02341-1

Interferon-mediated NK cell activation increases cytolytic activity against T follicular helper cells and limits antibody response to SARS-CoV-2

Nat Immunol. 2025 Dec;26(12):2201-2217. doi: 10.1038/s41590-025-02341-1. Epub 2025 Nov 21.

Authors

Izumi de Los Rios Kobara^{1

2}, Radeesha Jayewickreme^{1

2}, Madeline J Lee^{1

2}, Aaron J Wilk^{1

2

3}; Stanford COVID-19 Biobank; Andra L Blomkalns⁴, Kari C Nadeau^{5

6}, Samuel Yang⁴, Angela J Rogers⁷, Catherine A Blish^{8

9

10

11}

Affiliations

¹ Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
² Stanford Immunology Program, Stanford University School of Medicine, Stanford, CA, USA.
³ Stanford Medical Scientist Training Program, Stanford University School of Medicine, Stanford, CA, USA.
⁴ Department of Emergency Medicine, Stanford University School of Medicine, Stanford, CA, USA.
⁵ Department of Environmental Health, Harvard School of Public Health, Boston, MA, USA.
⁶ Department of Medicine and Division of Allergy and Inflammation, Beth Israel Deaconess Hospital, Boston, MA, USA.
⁷ Division of Pulmonary, Allergy and Critical Care Medicine, Stanford University, Stanford, CA, USA.
⁸ Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA. cblish@stanford.edu.
⁹ Stanford Immunology Program, Stanford University School of Medicine, Stanford, CA, USA. cblish@stanford.edu.
¹⁰ Stanford Medical Scientist Training Program, Stanford University School of Medicine, Stanford, CA, USA. cblish@stanford.edu.
¹¹ Chan Zuckerberg Biohub, San Francisco, CA, USA. cblish@stanford.edu.

Abstract

Natural killer (NK) cells are innate lymphocytes known for their ability to kill infected or malignant cells, but they have an overlooked role in regulating antibody responses. In mice, NK cells can kill T follicular helper (T_FH) cells, decreasing somatic hypermutation and antibody titers. Although human NK cell activation correlates with poor vaccine response, the mechanisms of NK cell regulation of adaptive immunity in humans are poorly understood. Here we found that, in ancestral severe acute respiratory syndrome coronavirus 2 infection, individuals with the broadest neutralization profile had fewer NK cells that expressed inhibitory and immaturity markers, whereas NK cells from narrow neutralizers were highly activated and expressed interferon-stimulated genes. ISG-mediated activation in NK cells from healthy donors increased cytotoxicity toward induced T_FH-like cells via NKG2D and NKp30. This work reveals that NK cell activation and dysregulated inflammation play a role in poor antibody response to severe acute respiratory syndrome coronavirus 2 and opens exciting avenues for designing improved vaccines and adjuvants to target emerging pathogens.

MeSH terms

Adult
Antibodies, Viral* / immunology
Antibody Formation* / immunology
COVID-19* / immunology
Cytotoxicity, Immunologic
Female
Humans
Interferons* / immunology
Interferons* / metabolism
Killer Cells, Natural* / immunology
Lymphocyte Activation* / immunology
Male
NK Cell Lectin-Like Receptor Subfamily K / immunology
NK Cell Lectin-Like Receptor Subfamily K / metabolism
SARS-CoV-2* / immunology
T Follicular Helper Cells* / immunology

Substances

Antibodies, Viral
Interferons
NK Cell Lectin-Like Receptor Subfamily K

Abstract

MeSH terms

Substances

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