Long Qiuyue, Song Shixu, Xue Jianbo, Yu Wenyi, Zheng Yaolin, Li Jiwei, Wu Jing, Hu Xiaoyi, Jiang Mingzheng, Ye Hongli, Zheng Binghan, Wang Minghui, Wu Fangfang, Li Ke, Gao Zhancheng, Zheng Yali
Department of Respiratory, Critical Care and Sleep Medicine, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China.
Institute of Chest and Lung Diseases, Xiang'an Hospital of Xiamen University, Xiamen, China.
Front Immunol. 2025 Apr 30;16:1577803. doi: 10.3389/fimmu.2025.1577803. eCollection 2025.
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.
We utilized flow cytometry to analyze peripheral immune cells from healthy, bacterial pneumonia patients, and COVID-19 patients. The expansion of activated T cells (CD38HLA-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.
We revealed a significant increase in CD38HLA-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 CD38HLA-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.
We identified the selective expansion of CD38HLA-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.
新型冠状病毒肺炎（COVID-19）大流行仍是一项全球卫生挑战。重症病例对标准治疗的反应往往不佳，这凸显了新型治疗靶点和早期预测生物标志物的必要性。
我们利用流式细胞术分析健康人、细菌性肺炎患者和COVID-19患者的外周免疫细胞。检测活化T细胞（CD38HLA-DR）、单核细胞和髓系来源抑制细胞（MDSC）的扩增情况，并将其与临床结局相关联，以评估预后潜力。应用单细胞RNA测序（scRNA-seq）来表征与预后相关的关键细胞亚群，并阐明其在COVID-19中的表型。
我们发现非存活COVID-19患者中CD38HLA-DR T细胞显著增加，将其确定为28天死亡率的独立危险因素。scRNA-seq分析将CD38HLA-DR T细胞鉴定为一个终末分化的、调节性T细胞样亚群，具有激活和耗竭特征。该亚群在所有T细胞亚群中呈现最高的白细胞介素-6（IL-6）和白细胞介素-10（IL-10）mRNA水平。进一步的功能分析表明其增强的主要组织相容性复合体II类（MHC-II）交叉信号传导以及相应富集的细胞骨架重排过程。此外，通过scRNA-seq发现CD38+HLA-DR+ T细胞中烟酰胺腺嘌呤二核苷酸（NAD）代谢失调，同时COVID-19患者血清中腺苷水平升高而NAD水平降低。
我们确定CD38HLA-DR T细胞的选择性扩增是COVID-19结局的一种新型预后指标。这些细胞独特的激活-耗竭表型及其对NAD代谢的影响，为COVID-19免疫发病机制提供了新的见解。
