ABSTRACT While the role of CD8 + T cells in influenza clearance is established, their contribution to pathological lung injury is increasingly appreciated. To explore if protective versus pathological functions can be linked to CD8 + T cell subpopulations, we dissected their responses in influenza-infected murine lungs. Our single-cell RNASeq (scRNAseq) analysis revealed significant diversity in CD8 + T cell subpopulations during peak viral load vs. infection-resolved state. While enrichment of Cxcr3 hi CD8 + T effector (T eff ) subset was associated with a more robust cytotoxic response, both CD8 + T eff and CD8 + T central memory (T CM ) exhibited equally potent effector potential. The scRNAseq analysis identified unique regulons regulating the cytotoxic response in CD8 + T cells. The neutralization of CXCR3 mitigated lung injury without affecting viral clearance. IFN-γ was dispensable to regulate the cytotoxic response of Cxcr3 hi CD8 + T cells. Collectively, our data imply that CXCR3 interception could have a therapeutic effect in preventing influenza-linked lung injury. TEASER The CXCR3 expressing CD8+ T cell subset causes severe lung pathology and exacerbates disease severity without affecting viral clearance during influenza infection

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