Interferon-mediated NK cell activation is associated with limited neutralization breadth during SARS-CoV-2 infection — ASN Events
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Interferon-mediated NK cell activation is associated with limited neutralization breadth during SARS-CoV-2 infection (#262)

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 4 , Andra L Blomkalns 5 , Kari C Nadeau 6 7 , Samuel Yang 5 , Angela J Rogers 8 , Catherine A Blish 1 2 3 9
  1. Department of Medicine, Stanford University School of Medicine, Stanford, CA, United States
  2. Immunology Program, Stanford University School of Medicine, Stanford, CA, United States
  3. Stanford Medical Scientist Training Program, Stanford University School of Medicine, Stanford , CA, United States
  4. Stanford University, Stanford, CA, United States
  5. Department of Emergency Medicine, Stanford University School of Medicine, Stanford, CA, United States
  6. Department of Environmental Health, Harvard School of Public Health, Boston, MA, United States
  7. Department of Medicine and Division of Allergy and Inflammation, Beth Israel Deaconess Hospital, Boston, MA, United States
  8. Division of Pulmonary, Allergy and Critical Care Medicine, Stanford University School of Medicine, Stanford, CA, United States
  9. Chan Zuckerberg Biohub, San Francisco, CA, United States

Best known for their ability to kill infected or malignant cells, natural killer (NK) cells are also underappreciated regulators of the antibody response to viral infection. In mice, NK cells can kill T follicular helper (Tfh) cells, decreasing somatic hypermutation and vaccine responses. Although human NK cell activation correlates with poor vaccine response, the mechanisms of human NK cell regulation of adaptive immunity are poorly understood, and it is not known whether NK cells influence the cross reactive response to emerging viral variants. In ancestral SARS-CoV-2 infection, the antibody response is highly variable; some infected individuals develop neutralizing responses against distant variants whereas others fail to neutralize ancestral virus. We hypothesized that NK cells may regulate adaptive immune cells during SARS-CoV-2 infection and result in decreased antibody breadth against variants.  Individuals infected with ancestral SARS-CoV-2 from across the severity spectrum were profiled by single-cell RNA-sequencing, cyTOF, and pseudovirus neutralization breadth against variants of concern. We found distinct phenotypes in broad neutralizers, who were capable of neutralizing ancestral, Alpha, Beta, and Delta, when compared to narrow neutralizers (individuals who neutralized <4 variants). Narrow neutralizers had profound upregulation of interferon-stimulated genes (ISGs) across the immune system. This ISG signature was observed most strongly in NK cells, which were highly activated and cytotoxic. Conversely, NK cells from broad neutralizers expressed inhibitory and immaturity markers. In vitro, ISG-mediated activation in NK cells from healthy donors increased killing of and functional responses to induced Tfh-like cells which may underlie unfavorable antibody responses. Our study represents the first association between NK cell responses and antibody breadth in acute human viral infection. This work reveals that NK cell activation and dysregulated inflammation may play a role in poor antibody response to SARS-CoV-2 and opens exciting avenues for designing improved vaccines and adjuvants to target emerging pathogens.