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

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 Cxcr3hi CD8+ T effector (Teff) subset was associated with a more robust cytotoxic response, both CD8+ Teff and CD8+ T central memory (TCM) 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 Cxcr3hi CD8+ T cells. Collectively, our data imply that CXCR3 interception could have a therapeutic effect in preventing influenza-linked lung injury.TEASERThe CXCR3 expressing CD8+ T cell subset causes severe lung pathology and exacerbates disease severity without affecting viral clearance during influenza infection

Mucosal immune responses to infection and vaccination in the respiratory tract

“…Short-lived, cytotoxic CD8 + T cells recognize class I MHC-bound peptide (pMHC) and mediate targeted killing of infected cells through secretion of cytolytic enzymes. Dysregulation of these cells during infection can lead to lung damage, as was observed in a recent preprint by Guo et al., demonstrating that overproduction of CXCR3 drives CD8 + T cell-dependent lung pathology during influenza infection ( Guo et al., 2022 ). In other contexts, CD8 + T cells are also important producers of anti-inflammatory cytokines such as IL10.…”

Host Recovery from Respiratory Viral Infection

“…During acute infection, T cells secrete numerous proinflammatory cytokines, including TNF-α and IFN-γ, contributing to pulmonary inflammation typically aimed at viral clearance (38,95). However, several T cell subsets and associated cytokines contribute to lung pathology and poor outcomes, evidenced by the enrichment of CXCR3 + CD8 + T cells during influenza infection (96) and virus-specific overactivated CD4 + T cells in COVID-19 (41,97). Moreover, pathogenic Th1 and Th17 cells with high expression of GM-CSF are associated with increased pulmonary inflammation (84,98).…”