Understanding the mechanism that leads to immune dysfunction in severe coronavirus disease 2019 (COVID-19) is crucial for the development of effective treatment. Here, using single-cell RNA sequencing, we characterized the peripheral blood mononuclear cells (PBMCs) from uninfected controls and COVID-19 patients and cells in paired broncho-alveolar lavage fluid (BALF). We found a close association of decreased dendritic cells (DCs) and increased monocytes resembling myeloid-derived suppressor cells (MDSCs), which correlated with lymphopenia and inflammation in the blood of severe COVID-19 patients. Those MDSC-like monocytes were immune-paralyzed. In contrast, monocyte-macrophages in BALFs of COVID-19 patients produced massive amounts of cytokines and chemokines, but secreted little interferons. The frequencies of peripheral T cells and NK cells were significantly decreased in severe COVID-19 patients, especially for innate-like T and various CD8⁺ T cell subsets, compared to healthy controls. In contrast, the proportions of various activated CD4⁺ T cell subsets among the T cell compartment, including Th1, Th2, and Th17-like cells were increased and more clonally expanded in severe COVID-19 patients. Patients’ peripheral T cells showed no sign of exhaustion or augmented cell death, whereas T cells in BALFs produced higher levels of IFNG, TNF, CCL4, CCL5, etc. Paired TCR tracking indicated abundant recruitment of peripheral T cells to the severe patients’ lung. Together, this study comprehensively depicts how the immune cell landscape is perturbed in severe COVID-19.

了解导致 2019 年严重冠状病毒病 (COVID-19) 免疫功能障碍的机制对于开发有效的治疗方法至关重要。在这里，我们使用单细胞 RNA 测序，对未感染对照和 COVID-19 患者的外周血单核细胞 (PBMC) 以及配对支气管肺泡灌洗液 (BALF) 中的细胞进行了表征。我们发现树突状细胞 (DC) 减少和类似于骨髓源性抑制细胞 (MDSC) 的单核细胞增加密切相关，这与重症 COVID-19 患者血液中的淋巴细胞减少和炎症相关。那些 MDSC 样单核细胞处于免疫麻痹状态。相比之下，COVID-19 患者 BALF 中的单核巨噬细胞产生大量细胞因子和趋化因子，但分泌很少的干扰素。与健康对照相比，重症 COVID-19 患者的外周 T 细胞和 NK 细胞频率显着降低，尤其是先天样 T 和各种 CD8 ⁺ T 细胞亚群。相比之下，在重症 COVID-19 患者中，T 细胞区室中各种活化的 CD4 ⁺ T 细胞亚群（包括 Th1、Th2 和 Th17 样细胞）的比例有所增加，并且克隆性扩张程度更高。患者的外周 T 细胞没有表现出衰竭或细胞死亡增加的迹象，而 BALF 中的 T 细胞产生了更高水平的IFNG 、 TNF 、 CCL4 、 CCL5等。配对 TCR 追踪表明外周 T 细胞大量招募到重症患者的肺部。总之，这项研究全面描述了严重的 COVID-19 中免疫细胞格局如何受到干扰。