Abstract Cytotoxic T cells can promote protective immunity or exacerbate lung damage during influenza infections. Fine-tuning the functional activity of cytotoxic T cells in situ within influenza-infected lungs is a potential strategy to balance immunity and immunopathology. Using a murine model of influenza, we found that CXCR4 expression strongly correlated with cytotoxic T cell degranulation and that inhibition of CXCR4 reduced the degranulation of cytotoxic T cells in vitro and in vivo. Live tissue imaging revealed that influenza-specific T cells had prolonged dwell times when they were in regions with high levels of influenza antigen. Inhibition of CXCR4 led to increased T cell speed and decreased stop times in influenza-high areas. Moreover, inhibition of CXCR4 expedited the recovery of flu-infected mice. These data identify CXCR4 as a positive regulator of the stop-signal in lung-infiltrating CD8+ T cells and suggest that targeting this pathway could enhance recovery from influenza-induced weight loss.
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