The chemokine receptor CXCR3 promotes CD8+ T cell dependent lung pathology during influenza pathogenesis

Purpose: A growing body of evidence highlights the association of exuberant CD8+ T cell responses with influenza acute lung injury. Given their indispensable role in viral clearance, we studied the double-edged function of CD8+ T cells as a bridge between infection resolution and lung pathology. Methods: we performed scRNA-Seq to study the cellular heterogeneity and regulation of cellular response in CD8+ T cells during peak viral (day 7) and post-viral resolution phase (day 14). Results: Our single-cell RNA-Seq data reveal significant differences in CD8+ T cell heterogeneity during different stages of influenza infection (peak viral load vs. infection resolved state). While CXCR3hi CD8+ T effector memory (Tem) was associated with a more robust cytotoxic response (compared to CXCR3low CD8+ T central memory, Tcm), both CD8+ Tem and Tcm exhibited equally potent effector function. The ablation of CXCR3 mitigates lung injury without affecting viral clearance. IFN-gamma was dispensable to the recruitment and regulation of cytotoxic response of CXCR3+ CD8+ T cells. Using scRNAseq, we identified unique regulons associated with regulating cytotoxic response in CXCR3hi CD8+ T cells. Conclusions: Collectively, our data identify CXCR3 as a potential therapeutic target to curb lung injury during influenza pathogenesis. scRNAseq profiles of mock, 7 days and 14 days post-IAV infection