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Nat Immunol
. 2025 Nov 21.
doi: 10.1038/s41590-025-02341-1. Online ahead of print. 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 1 2 , Radeesha Jayewickreme 1 2 , Madeline J Lee 1 2 , Aaron J Wilk 1 2 3 ; Stanford COVID-19 Biobank; Andra L Blomkalns 4 , Kari C Nadeau 5 6 , Samuel Yang 4 , Angela J Rogers 7 , Catherine A Blish 8 9 10 11
Affiliations
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 (TFH) 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 TFH-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.
. 2025 Nov 21.
doi: 10.1038/s41590-025-02341-1. Online ahead of print. 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 1 2 , Radeesha Jayewickreme 1 2 , Madeline J Lee 1 2 , Aaron J Wilk 1 2 3 ; Stanford COVID-19 Biobank; Andra L Blomkalns 4 , Kari C Nadeau 5 6 , Samuel Yang 4 , Angela J Rogers 7 , Catherine A Blish 8 9 10 11
Affiliations
- PMID: 41272165
- DOI: 10.1038/s41590-025-02341-1
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 (TFH) 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 TFH-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.