Natural killer (NK) cell antibody-dependent cellular cytotoxicity (ADCC) contributes to effective antiviral immunity, yet the relative contribution of NK cell-intrinsic factors and antibodies in mediating these responses remains poorly understood. Here, we combined functional ADCC assays with single-cell transcriptomics of peripheral NK cells from COVID-19 participants. Our analysis revealed distinct transcriptional programs between participants with different ADCC response levels: NK cells from participants with lower ADCC responses upregulated proliferation pathways, while those with high ADCC responses showed enhanced expression of interferon-stimulated genes and NKG2D. Blocking NKG2D significantly reduced NK cell ADCC degranulation and cytokine responses. Paradoxically, greater interferon-mediated NK cell activation was associated with reduced proficiency of participants' antibodies to mediate ADCC, suggesting a regulatory checkpoint mechanism. These findings enhance our understanding of the molecular determinants of ADCC responses and provide novel insights into leveraging these responses for more effective vaccination and therapeutic strategies.
Keywords: COVID-19; NKG2D; antibody-dependent cellular cytotoxicity; natural killer cells.
© The Author(s) 2026. Published by Oxford University Press on behalf of Society for Leukocyte Biology.