Keratinocyte-Mediated Activation of the Cytokine TGF-β Maintains Skin Recirculating Memory CD8⁺ T Cells

Regulated activation of the cytokine TGF-β by integrins α_vβ₆ and α_vβ₈ expressed on keratinocytes is required for residence of epidermal-resident memory T cells, but whether skin-derived signals also affect recirculating memory cells in the skin remains unclear. Here, we show that after resolution of skin vaccinia virus (VV)infection, antigen-specific circulating memory CD8⁺ T cells migrated into skin. In mice lacking α_vβ₆ and α_vβ₈ integrins (Itgb6^−/−Itgb8^fl/fl-K14-cre), the absence of epidermal-activated TGF-β resulted in a gradual loss of E- or P-selectin-binding central and peripheral memory populations, which were rescued when skin entry was inhibited. Skin recirculating memory cells were required for optimal host defense against skin VV infection. These data demonstrate that skin migration can persist after resolution of local skin infection and that the cytokine environment within this nonlymphoid tissue shapes the differentiation state and persistence of the central and peripheral memory-T-cell pool.