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

The dual role of CD8⁺ T cells in influenza control and lung pathology is increasingly appreciated. To explore whether protective and pathological functions can be linked to specific subsets, we dissected CD8⁺ T responses in influenza-infected murine lungs. Our single-cell RNA-sequencing (scRNA-seq) analysis revealed notable diversity in CD8⁺ T subpopulations during peak viral load and infection-resolved state. While enrichment of a Cxcr3^hi CD8⁺ T effector subset was associated with a more robust cytotoxic response, both CD8⁺ T effector and central memory exhibited equally potent effector potential. The scRNA-seq analysis identified unique regulons regulating the cytotoxic response in CD8⁺ T cells. The late-stage CD8⁺ T blockade in influenza-cleared lungs or continuous CXCR3 blockade mitigated lung injury without affecting viral clearance. Furthermore, adoptive transfer of wild-type CD8⁺ T cells exacerbated influenza lung pathology in Cxcr3^-/- mice. Collectively, our data imply that CXCR3 interception could have a therapeutic effect in preventing influenza-linked lung injury.