The chemokine receptor CXCR3 promotes CD8 <sup>+</sup> T cell–dependent lung pathology during influenza pathogenesis
Kai Guo, Dan Justin Kalenda Yombo, Zhihan Wang, Zahrasadat Navaeiseddighi, Jintao Xu, Taylor Schmit, Nassem Ahamad, Jitendra Kumar Tripathi, Bony De Kumar, Ramkumar Mathur, Junguk Hur, Jie Sun, Michal A. Olszewski, Nadeem Khan
Abstract
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.