Cytokine storm promoting T cell exhaustion in severe COVID-19 revealed by single cell sequencing data analysis.

Background: Evidence has suggested that cytokine storms may be associated with T cell exhaustion (TEX) in COVID-19. However, the interaction mechanism between cytokine storms and TEX remains unclear. Methods: With the aim of dissecting the molecular relationship of cytokine storms and TEX through single-cell RNA sequencing data analysis, we identified 14 cell types from bronchoalveolar lavage fluid of COVID-19 patients and healthy people. We observed a novel subset of severely exhausted CD8 T cells (Exh T_CD8) that co-expressed multiple inhibitory receptors, and two macrophage subclasses that were the main source of cytokine storms in bronchoalveolar. Results: Correlation analysis between cytokine storm level and TEX level suggested that cytokine storms likely promoted TEX in severe COVID-19. Cell-cell communication analysis indicated that cytokines (e.g. CXCL10, CXCL11, CXCL2, CCL2, and CCL3) released by macrophages acted as ligands and significantly interacted with inhibitory receptors (e.g. CXCR3, DPP4, CCR1, CCR2, and CCR5) expressed by Exh T_CD8. These interactions formed the cytokine-receptor axes, which were also verified to be significantly correlated with cytokine storms and TEX in lung squamous cell carcinoma. Conclusions: Cytokine storms may promote TEX through cytokine-receptor axes and be associated with poor prognosis in COVID-19. Blocking cytokine-receptor axes may reverse TEX. Our finding provides novel insights into TEX in COVID-19 and new clues for cytokine-targeted immunotherapy development.