IL-4 impairs the formation of skin-resident memory CD8⁺ T cells

Local cytokines, including TGFβ, drive CD8⁺ tissue-resident memory T (T_RM) cell differentiation and long-term persistence within tissues. However, the signals that prevent CD8⁺ T_RM cell formation are not well defined. Here we found that IL-4 suppressed CD8⁺ T cell acquisition of an epithelial T_RM cell phenotype. IL-4 inhibited the expression of TGFβ-induced CD103 and CD49a and increased the expression of Eomes by activated CD8⁺ T cells in vitro and in vivo. This change in phenotype was correlated with prolonged downregulation of TGFβRII, decreased expression of pSmad2/3 and increased expression of inhibitory Smad7. Naive CD8⁺ T cells exposed to IL-4 during activation exhibited impaired cutaneous CD103⁺CD8⁺ T_RM cell formation. Additionally, IL-4 produced within atopic dermatitis lesions decreased the expression of CD103 in infiltrating CD8⁺ T cells and reduced CD8⁺ T_RM cell formation, resulting in reduced protection from cutaneous herpes simplex virus infection. Together, these findings reveal that IL-4 decreases the responsiveness of CD8⁺ T cells to TGFβ, resulting in impaired formation of CD8⁺ T_RM cells and impaired CD8⁺ T_RM cell-mediated protection from local infection.