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

• Published in: Science advances 2024-01, Vol.10 (1), p.eadj1120
• Main Authors: Guo, Kai, Yombo, Dan J K, Wang, Zhihan, Navaeiseddighi, Zahrasadat, Xu, Jintao, Schmit, Taylor, Ahamad, Nassem, Tripathi, Jitendra, De Kumar, Bony, Mathur, Ramkumar, Hur, Junguk, Sun, Jie, Olszewski, Michal A, Khan, Nadeem
• Format: Article
• Language: English
• Subjects: Animals; CD8-Positive T-Lymphocytes; Humans; Immunology; Influenza, Human; Lung; Lung Injury; Mice; Mice, Inbred C57BL; Mice, Knockout; Receptors, Chemokine; SciAdv r-articles; Virology
• ISSN: 2375-2548; 2375-2548
• DOI: 10.1126/sciadv.adj1120

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 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.