CXCR3‐deficiency protects influenza‐infected CCR5‐deficient mice from mortality

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Abstract
Mice lacking the chemokine receptor CCR5 are susceptible to mortality from a normally non‐lethal influenza infection. Here we found that CXCR3‐deficiency rescued CCR5‐deficient (CCR5−/−) mice from influenza‐induced mortality. The number of mononuclear phagocytes in the airways was transiently increased in CCR5−/− mice but not in CXCR3‐CCR5 double‐deficient mice. Antigen‐specific CXCR3‐CCR5 double‐deficient CD8 effector cells were less efficient at entering the airways compared with WT or CCR5−/− CD8 effector cells. The decrease in inflammatory cell infiltrates in CXCR3‐CCR5 double‐deficient‐infected mice correlated with a decrease in CCL2 and IFN‐γ production in the airways. Finally, CXCR3‐CCR5 double‐deficient mice that survived the primary viral challenge were protected from a lethal secondary challenge, indicating that T‐cell‐mediated protective memory was not compromised in mice lacking these chemokine receptors. In conclusion, CXCR3‐deficiency attenuated the lethal cellular immune response in CCR5−/− influenza‐infected mice without hindering viral clearance or long‐term immunity.