Interferon stimulation and NKG2D expression drive enhanced natural killer cell antibody-dependent cellular cytotoxicity against viral infections

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 remain 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.