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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.<\/jats:p>","DOI":"10.1093\/jleuko\/qiag019","type":"journal-article","created":{"date-parts":[[2026,2,1]],"date-time":"2026-02-01T12:32:13Z","timestamp":1769949133000},"source":"Crossref","is-referenced-by-count":3,"title":["Interferon stimulation and NKG2D expression drive enhanced natural killer cell antibody-dependent cellular cytotoxicity against viral infections"],"prefix":"10.1093","volume":"118","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5064-140X","authenticated-orcid":false,"given":"Leslie","family":"Chan","sequence":"first","affiliation":[{"name":"Stanford Immunology Program, Stanford University School of Medicine , BioMedical Innovations Building, 240 Pasteur Drive, Stanford, CA 94305 ,","place":["United States"]},{"name":"Department of Medicine, Stanford University School of Medicine , 300 Pasteur Drive, Edwards Building Suite R106, Stanford, CA 94305 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kassandra","family":"Pinedo","sequence":"additional","affiliation":[{"name":"Department of Medicine, Stanford University School of Medicine , 300 Pasteur Drive, Edwards Building Suite R106, Stanford, CA 94305 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1123-9036","authenticated-orcid":false,"given":"Samuel","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Emergency Medicine, Stanford University School of Medicine , 900 Welch Road, Suite 350, Stanford, CA 94305 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andra L","family":"Blomkalns","sequence":"additional","affiliation":[{"name":"Department of Emergency Medicine, Stanford University School of Medicine , 900 Welch Road, Suite 350, Stanford, CA 94305 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kari C","family":"Nadeau","sequence":"additional","affiliation":[{"name":"Department of Medicine, Stanford University School of Medicine , 300 Pasteur Drive, Edwards Building Suite R106, Stanford, CA 94305 ,","place":["United States"]},{"name":"Department of Environmental Health, Harvard Chan School of Public Health and Department of Medicine, Harvard Medical School , 677 Huntington Avenue, Boston, MA 02115 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela J","family":"Rogers","sequence":"additional","affiliation":[{"name":"Department of Medicine, Stanford University School of Medicine , 300 Pasteur Drive, Edwards Building Suite R106, Stanford, CA 94305 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine A","family":"Blish","sequence":"additional","affiliation":[{"name":"Department of Medicine, Stanford University School of Medicine , 300 Pasteur Drive, Edwards Building Suite R106, Stanford, CA 94305 ,","place":["United States"]},{"name":"Stanford Medical Scientist Training Program, Stanford University School of Medicine , 300 Pasteur Drive, Edwards Building Suite 133, Stanford, CA 94305 ,","place":["United States"]},{"name":"Chan Zuckerberg Biohub , 499 Illinois St, San Francisco, CA 94185 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,2,4]]},"reference":[{"key":"2026021711215697500_qiag019-B1","doi-asserted-by":"publisher","first-page":"6127","DOI":"10.1128\/JVI.00347-16","article-title":"Comparison of antibody-dependent cell-mediated cytotoxicity and virus neutralization by HIV-1 Env-specific monoclonal antibodies","volume":"90","author":"Von Bredow","year":"2016","journal-title":"J 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