{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,31]],"date-time":"2026-10-31T17:28:27Z","timestamp":1793467707797,"version":"4.5.0"},"reference-count":50,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,9,9]],"date-time":"2021-09-09T00:00:00Z","timestamp":1631145600000},"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>The global outbreak of coronavirus disease 2019 (COVID-19) has turned into a worldwide public health crisis and caused more than 100,000,000 severe cases. Progressive lymphopenia, especially in T cells, was a prominent clinical feature of severe COVID-19. Activated HLA-DR<jats:sup>+<\/jats:sup>CD38<jats:sup>+<\/jats:sup> CD8<jats:sup>+<\/jats:sup> T cells were enriched over a prolonged period from the lymphopenia patients who died from Ebola and influenza infection and in severe patients infected with SARS-CoV-2. However, the CD38<jats:sup>+<\/jats:sup>HLA-DR<jats:sup>+<\/jats:sup> CD8<jats:sup>+<\/jats:sup> T population was reported to play contradictory roles in SARS-CoV-2 infection.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>A total of 42 COVID-19 patients, including 32 mild or moderate and 10 severe or critical cases, who received care at Beijing Ditan Hospital were recruited into this retrospective study. Blood samples were first collected within 3 days of the hospital admission and once every 3\u20137 days during hospitalization. The longitudinal flow cytometric data were examined during hospitalization. Moreover, we evaluated serum levels of 45 cytokines\/chemokines\/growth factors and 14 soluble checkpoints using Luminex multiplex assay longitudinally.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We revealed that the HLA-DR<jats:sup>+<\/jats:sup>CD38<jats:sup>+<\/jats:sup> CD8<jats:sup>+<\/jats:sup> T population was heterogeneous, and could be divided into two subsets with distinct characteristics: HLA-DR<jats:sup>+<\/jats:sup>CD38<jats:sup>dim<\/jats:sup> and HLA-DR<jats:sup>+<\/jats:sup>CD38<jats:sup>hi<\/jats:sup>. We observed a persistent accumulation of HLA-DR<jats:sup>+<\/jats:sup>CD38hi CD8<jats:sup>+<\/jats:sup> T cells in severe COVID-19 patients. These HLA-DR<jats:sup>+<\/jats:sup>CD38<jats:sup>hi<\/jats:sup> CD8<jats:sup>+<\/jats:sup> T cells were in a state of overactivation and consequent dysregulation manifested by expression of multiple inhibitory and stimulatory checkpoints, higher apoptotic sensitivity, impaired killing potential, and more exhausted transcriptional regulation compared to HLA-DR<jats:sup>+<\/jats:sup>CD38<jats:sup>dim<\/jats:sup> CD8<jats:sup>+<\/jats:sup> T cells. Moreover, the clinical and laboratory data supported that only HLA-DR<jats:sup>+<\/jats:sup>CD38<jats:sup>hi<\/jats:sup> CD8<jats:sup>+<\/jats:sup> T cells were associated with systemic inflammation, tissue injury, and immune disorders of severe COVID-19 patients.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our findings indicated that HLA-DR<jats:sup>+<\/jats:sup>CD38<jats:sup>hi<\/jats:sup> CD8<jats:sup>+<\/jats:sup> T cells were correlated with disease severity of COVID-19 rather than HLA-DR<jats:sup>+<\/jats:sup>CD38<jats:sup>dim<\/jats:sup> population.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2021.735125","type":"journal-article","created":{"date-parts":[[2021,9,9]],"date-time":"2021-09-09T09:59:59Z","timestamp":1631181599000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":77,"title":["Persistent High Percentage of HLA-DR+CD38high CD8+ T Cells Associated With Immune Disorder and Disease Severity of COVID-19"],"prefix":"10.3389","volume":"12","author":[{"given":"Juan","family":"Du","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lirong","family":"Wei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guoli","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingxi","family":"Hua","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yao","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Di","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai","family":"Han","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yonghong","family":"Yan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chuan","family":"Song","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Song","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henghui","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junyan","family":"Han","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingyuan","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaxian","family":"Kong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,9,9]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"497","DOI":"10.1016\/S0140-6736(20)30183-5","article-title":"Clinical Features of Patients Infected With 2019 Novel Coronavirus in Wuhan, China","volume":"395","author":"Huang","year":"2020","journal-title":"Lancet"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.202003-0543OC","article-title":"Clinical Features of 85 Fatal Cases of COVID-19 From Wuhan. 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