AbstractTissue resident memory CD8+ T cells (TRM) persist long-term in lymphoid and non-lymphoid tissues to provide rapid, local defense against pathogens and tumors. Tissue cytokines drive the formation and persistence of CD8+ TRM. However, whether the local microenvironment can inhibit TRM formation is largely unknown. Individuals suffering from conditions associated with T helper 2 (Th2)-type immune responses, such as atopic dermatitis, asthma, and some cancers, present impaired anti-viral or anti-tumor responses. We hypothesize that Th2 cytokines inhibit the formation and/or persistence of CD8+ TRM. We demonstrate that Th2 cell supernatant downregulated TGF-β-induced CD103 expression on in vitro- and in vivo- activated CD8+ T cells in an IL-4- and Stat6-dependent manner. Moreover, IL-4 induced Eomes expression by TGF-β-stimulated CD8+ T cells. In vivo, more CD8+CD103+ TRM populated the skin of Il4ra−/− and Stat6−/− mice compared to wild-type mice at homeostasis. Additionally, CD8+ T cell activation in the presence of IL-4 impaired subsequent CD8+ TRM formation; IL-4-exposed CD8+ T cells expressed decreased CD103 in a mouse model of cutaneous inflammation, and these cells failed to persist within the skin at memory time-points. These data suggest that IL-4 counters TGF-β-mediated signals to inhibit CD8+ TRM formation/persistence and may allow identification of novel treatments to boost anti-tumor immunity and anti-viral responses in patients with type 2 inflammation.