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 COVID19.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.