{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T20:14:09Z","timestamp":1792181649282,"version":"4.4.0"},"reference-count":53,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,4,30]],"date-time":"2025-04-30T00:00:00Z","timestamp":1745971200000},"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 COVID-19 pandemic remains a global health challenge. Severe cases often respond poorly to standard treatments, highlighting the necessity for novel therapeutic targets and early predictive biomarkers.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We utilized flow cytometry to analyze peripheral immune cells from healthy, bacterial pneumonia patients, and COVID-19 patients. The expansion of activated T cells (CD38<jats:sup>+<\/jats:sup>HLA-DR<jats:sup>+<\/jats:sup>), monocytes, and myeloid-derived suppressor cells (MDSCs) were detected and correlated with clinical outcomes to evaluate prognostic potential. The single-cell RNA sequencing (scRNA-seq) was applied to characterize the critical cell subset associated with prognosis and elucidate its phenotype in COVID-19.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We revealed a significant increase in CD38<jats:sup>+<\/jats:sup>HLA-DR<jats:sup>+<\/jats:sup> T cells in non-survivor COVID-19 patients, establishing them as an independent risk factor for 28-day mortality. The scRNA-seq analysis identified the CD38<jats:sup>+<\/jats:sup>HLA-DR<jats:sup>+<\/jats:sup> T cell as a terminally differentiated, Treg-like subset exhibiting both activation and exhaustion characteristics. This subset presented the highest IL-6 and IL-10 mRNA levels among all T-cell subsets. Further functional analysis demonstrated its enhanced major histocompatibility complex class II (MHC-II) cross-signaling and correspondingly enriched cytoskeletal rearrangement processes. In addition, there was dysregulated NAD<jats:sup>+<\/jats:sup> metabolism in CD38+HLA-DR+ T cells via scRNA-seq, accompanied by elevated adenosine and decreased NAD<jats:sup>+<\/jats:sup> levels in serums from COVID-19 patients.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>We identified the selective expansion of CD38<jats:sup>+<\/jats:sup>HLA-DR<jats:sup>+<\/jats:sup> T cells as a novel prognostic indicator for COVID-19 outcomes. These cells\u2019 unique activated-exhausted phenotype, along with their impact on NAD<jats:sup>+<\/jats:sup> metabolism, provides new insights into COVID-19 immunopathogenesis.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2025.1577803","type":"journal-article","created":{"date-parts":[[2025,4,30]],"date-time":"2025-04-30T04:13:35Z","timestamp":1745986415000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":10,"title":["The CD38+HLA-DR+ T cells with activation and exhaustion characteristics as predictors of severity and mortality in COVID-19 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