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While Natural Killer (NK) cells and CD4+\/CD8+ T cells mount distinct responses against SARS-CoV-2, the phenotypic and functional signatures distinguishing protective immunity from pathogenic immune dysfunction have yet to be defined. In the present study, we present a comparative analysis of NK cell and SARS-CoV-2-specific T cell immunity in unvaccinated symptomatic (SYMP) versus asymptomatic (ASYMP) COVID-19 patients. Using multicolor flow cytometry, we interrogated key immune checkpoints, the senescence marker CD57, differentiation status (CD45RA\/CCR7), exhaustion marker PD-1, and activation markers HLA-DR and CD38, across NK and T cell subsets from SYMP patients, ASYMP patients, and Healthy Donors (HD). SYMP COVID-19 patients harbor significantly elevated co-expression of exhaustion and senescence markers on both NK and T cells relative to ASYMP patients and HD controls. Within the T cell compartment, SYMP patients exhibit broad dysregulation across na\u00efve, central memory, effector memory, and terminally differentiated effector memory subsets, with CD57 enriched most prominently on CD8+ TEM and CD8+ TEMRA populations. While cytokine profiles did not significantly differ between ASYMP and SYMP patients, both groups showed markedly elevated pro-inflammatory TNF-\u03b1, IFN-\u03b3, IL-6, IL-8, and IL-17 compared to HD controls, underscoring systemic immune activation as a hallmark of SARS-CoV-2 infection regardless of clinical severity. Taken together, these findings suggest that NK and T cell exhaustion and senescence are correlates of severe COVID-19, highlighting potential targets for future mechanistic and therapeutic investigation.<\/jats:p>","DOI":"10.3390\/v18090940","type":"journal-article","created":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T12:41:18Z","timestamp":1788266478000},"page":"940","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["High Frequencies of Senescent and Exhausted Natural Killer Cells and SARS-CoV-2-Specific Memory CD8+ T Cells Distinguish Critically Ill from Asymptomatic Unvaccinated COVID-19 Patients"],"prefix":"10.3390","volume":"18","author":[{"given":"Ruchi","family":"Srivastava","sequence":"first","affiliation":[{"name":"Laboratory of Cellular and Molecular Immunology, Gavin Herbert Eye Institute, School of Medicine, University of California Irvine, Irvine, CA 92697, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3986-890X","authenticated-orcid":false,"given":"Swayam","family":"Prakash","sequence":"additional","affiliation":[{"name":"Laboratory of Cellular and Molecular Immunology, Gavin Herbert Eye Institute, School of Medicine, University of California Irvine, Irvine, CA 92697, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sweta","family":"Karan","sequence":"additional","affiliation":[{"name":"Laboratory of Cellular and Molecular Immunology, Gavin Herbert Eye Institute, School of Medicine, University of California Irvine, Irvine, CA 92697, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9468-2521","authenticated-orcid":false,"given":"Lbachir","family":"BenMohamed","sequence":"additional","affiliation":[{"name":"Laboratory of Cellular and Molecular Immunology, Gavin Herbert Eye Institute, School of Medicine, University of California Irvine, Irvine, CA 92697, USA"},{"name":"Institute for Immunology, School of Medicine, University of California Irvine, Irvine, CA 92697, USA"},{"name":"TechImmune, Inc., Irvine, CA 92617, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1038\/s41579-025-01255-x","article-title":"SARS-CoV-2 variants: Biology, pathogenicity, immunity and control","volume":"24","author":"Uraki","year":"2026","journal-title":"Nat. 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