Individuals suffering from local Th2-type inflammatory diseases, including allergic asthma have increased risk for serious viral infections, but the cause is unclear. Defense against local infections relies on tissue resident memory CD8+ T cells (TRM) that reside within peripheral tissues and deliver rapid defense against pathogens and tumors. Following antigen challenge, CD8+ TRM secrete cytokines that activate innate cells, induce expression of anti-viral and anti-bacterial genes, and recruit circulating leukocytes for pathogen control. Given their central role in host protection, we hypothesize that impairment of CD8+ TRM contributes to severe infection in patients with atopic diseases. Our preliminary data demonstrate that IL-4 uniquely prevents TGF-- induced expression of the adhesion receptors CD49a and CD103 that are required for CD8+ TRM persistence within peripheral tissues. In parallel, in vivo studies reveal that exposure of CD8+ T cells to IL-4 decreases both their expression of CD103 as well as their accumulation within skin. Based on these preliminary data, we propose to extend these studies using a mouse model of allergic asthma to test the novel hypothesis that Th2 cytokines impair lung CD8+ TRM formation, persistence and defense against respiratory infection. Specifically, we propose to: 1) Determine the impact of a Th2-type microenvironment on lung CD8+ TRM formation/persistence, as well as on the phenotypic stability of established CD8+ TRM; and 2) Determine the consequence of IL-4 on lung CD8+ TRM-mediated protective immunity to influenza infection.