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Abstract
Mechanisms by which the immune system eliminates influenza virus involve the coordinated actions of the innate and adaptive immune systems. Influenza-specific CD8 T cells have been characterized as the primary mediators of viral clearance, and a crucial role for natural killer (NK) cells has also been described, namely that NK cells provide short-term control of viral replication prior to T cell activation. In order to fulfill their functions, both NK and CD8 T cells must migrate from the periphery to the site of infection, a process dependent on the production of chemokines and cytokines in the lung airways. This study shows that following influenza infection, localized increases in the homeostatic cytokine IL-15 are responsible for the migration and accumulation of both NK cells and influenza-specific CD8 T cells in the lung airways. Entry of NK cells and CD8 T cells into the site of infection is delayed in the absence of IL-15, and this reduction in lymphocyte numbers results in disregulated control of early viral replication. By the same principle, viral control can be therapeutically enhanced via intranasal administration of exogenous IL-15 complexes. Additionally, continued administration of IL-15 complexes throughout the contraction phase of the anti-influenza CD8 T cell response magnifies the resultant CD8 T cell memory pool generated in situ and provides protection to heterosubtypic viral challenges, even though these cells themselves do not require IL-15 for long-term maintenance. Our data suggest that mucosally-generated memory CD8 T cells may be independent of IL-15 for their homeostasis. Together this work suggests that local deposits of IL-15 regulate the coordinated innate and adaptive immune responses to influenza and emphasizes different cytokine requirements by CD8 T cell responses to mucosal or systemic viral infections.