Role of $CD8^+$ T cells in immunopathogenesis of influenza A virus infection.

Abstract

$CD8^+$ T cells clear viruses through their two main effector functions: cytolysis and cytokine secretion. However, the factors controlling these antiviral effector activities in vivo at infection sites are poorly understood. In this study, we suggest that IL-15 induces highly cytotoxic effector $CD8^+$ T cells in the context of lethal influenza infection, which may contribute to lung injury. We studied $CD8^+$ T cell responses in murine influenza model, using lethal and non-lethal influenza virus. Unexpectedly, depletion of $CD8^+$ T cells rescued survival during lethal influenza infection, even without any difference in virus elimination. We found that highly cytotoxic $CD8^+$ T cells from the lethal influenza-infected lungs exerted strong granzyme B-dependent cytotoxicity, without $IFN-\gamma$ secretion (represented by $CD107a^{bright}IFN-$\gamma^-$ cells). Interestingly, the amount of IL-15 was increased in the lung during the lethal infection, and in vivo anti-IL-15 blocking reduced the frequency of $CD107a^{bright}IFN-$\gamma^-$ $CD8^+$ T cells subset. In addition, IL-15 deficiency resulted in improved survival during lethal influenza. To our surprise, the adoptive transfer of $CD8^+$ T cells from the lungs with lethal infection caused severe lung injury in mice with non-lethal infection. With our present study, we report for the first time that highly cytotoxic $CD107a^{bright}IFN-$\gamma^-$ $CD8^+$ T cells may contribute to lung injury and lethality in murine influenza model. It appears that IL-15, highly produced during lethal influenza infection, is critically involved in their induction.