{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T20:00:02Z","timestamp":1791230402215,"version":"4.1.0"},"reference-count":106,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,3,28]],"date-time":"2024-03-28T00:00:00Z","timestamp":1711584000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Cross-reactive SARS-CoV-2-specific memory CD4<jats:sup>+<\/jats:sup> and CD8<jats:sup>+<\/jats:sup> T cells are present in up to 50% of unexposed, pre-pandemic, healthy individuals (UPPHIs). However, the characteristics of cross-reactive memory CD4<jats:sup>+<\/jats:sup> and CD8<jats:sup>+<\/jats:sup> T cells associated with subsequent protection of asymptomatic coronavirus disease 2019 (COVID-19) patients (i.e., unvaccinated individuals who never develop any COVID-19 symptoms despite being infected with SARS-CoV-2) remains to be fully elucidated.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>This study compares the antigen specificity, frequency, phenotype, and function of cross-reactive memory CD4<jats:sup>+<\/jats:sup> and CD8<jats:sup>+<\/jats:sup> T cells between common cold coronaviruses (CCCs) and SARS-CoV-2. T-cell responses against genome-wide conserved epitopes were studied early in the disease course in a cohort of 147 unvaccinated COVID-19 patients who were divided into six groups based on the severity of their symptoms.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Compared to severely ill COVID-19 patients and patients with fatal COVID-19 outcomes, the asymptomatic COVID-19 patients displayed significantly: (i) higher rates of co-infection with the 229E alpha species of CCCs (\u03b1-CCC-229E); (ii) higher frequencies of cross-reactive functional CD134<jats:sup>+<\/jats:sup>CD137<jats:sup>+<\/jats:sup>CD4<jats:sup>+<\/jats:sup> and CD134<jats:sup>+<\/jats:sup>CD137<jats:sup>+<\/jats:sup>CD8<jats:sup>+<\/jats:sup> T cells that cross-recognized conserved epitopes from \u03b1-CCCs and SARS-CoV-2 structural, non-structural, and accessory proteins; and (iii) lower frequencies of CCCs\/SARS-CoV-2 cross-reactive exhausted PD-1<jats:sup>+<\/jats:sup>TIM3<jats:sup>+<\/jats:sup>TIGIT<jats:sup>+<\/jats:sup>CTLA4<jats:sup>+<\/jats:sup>CD4<jats:sup>+<\/jats:sup> and PD-1<jats:sup>+<\/jats:sup>TIM3<jats:sup>+<\/jats:sup>TIGIT<jats:sup>+<\/jats:sup>CTLA4<jats:sup>+<\/jats:sup>CD8<jats:sup>+<\/jats:sup> T cells, detected both <jats:italic>ex vivo<\/jats:italic> and <jats:italic>in vitro<\/jats:italic>.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>These findings (i) support a crucial role of functional, poly-antigenic \u03b1-CCCs\/SARS-CoV-2 cross-reactive memory CD4<jats:sup>+<\/jats:sup> and CD8<jats:sup>+<\/jats:sup> T cells, induced following previous CCCs seasonal exposures, in protection against subsequent severe COVID-19 disease and (ii) provide critical insights into developing broadly protective, multi-antigen, CD4<jats:sup>+<\/jats:sup>, and CD8<jats:sup>+<\/jats:sup> T-cell-based, universal pan-Coronavirus vaccines capable of conferring cross-species protection.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2024.1343716","type":"journal-article","created":{"date-parts":[[2024,3,28]],"date-time":"2024-03-28T05:19:49Z","timestamp":1711603189000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":23,"title":["High frequencies of alpha common cold coronavirus\/SARS-CoV-2 cross-reactive functional CD4+ and CD8+ memory T cells are associated with protection from symptomatic and fatal SARS-CoV-2 infections in unvaccinated COVID-19 patients"],"prefix":"10.3389","volume":"15","author":[{"given":"Pierre-Gregoire","family":"Coulon","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Swayam","family":"Prakash","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nisha 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