The CD38(+)HLA-DR(+) T cells with activation and exhaustion characteristics as predictors of severity and mortality in COVID-19 patients.

BACKGROUND: 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. METHODS: 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(+)HLA-DR(+)), 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. RESULTS: We revealed a significant increase in CD38(+)HLA-DR(+) 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(+)HLA-DR(+) 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(+) metabolism in CD38+HLA-DR+ T cells via scRNA-seq, accompanied by elevated adenosine and decreased NAD(+) levels in serums from COVID-19 patients. CONCLUSIONS: We identified the selective expansion of CD38(+)HLA-DR(+) T cells as a novel prognostic indicator for COVID-19 outcomes. These cells' unique activated-exhausted phenotype, along with their impact on NAD(+) metabolism, provides new insights into COVID-19 immunopathogenesis.