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043 Keratinocyte-mediated activation of TGFβ maintains skin-recirculating memory CD8+ T cells

      Tissue-derived factors are critical for the development and persistence of skin-resident memory CD8+ T cells. Regulated activation of TGFβ by integrins αvβ6 and αvβ8 expressed on keratinocytes is required for residence of epidermal TRM that are lost in mice lacking these integrins (Itgb6-/-Itgb8ΔKC mice). However, whether skin-derived signals also affect recirculating memory cells that are only transiently in skin have been never noted. Here, we show that after resolution of skin vaccinia virus (VV) infection, antigen-specific circulating memory CD8+ T cells migrate into skin in an antigen- and inflammation-independent manner. In Itgb6-/-Itgb8ΔKC mice, the absence of activated TGFβ results in normal expansion and differentiation of CD8+ T cells but a gradual loss of E- or P-selectin binding central and peripheral memory populations from secondary lymphoid organs that results in reduced protection to VV skin challenge. Notably, pertussis toxin inhibition of skin entry of the memory cells rescues the loss of memory cells in Itgb6-/-Itgb8ΔKC mice. These data demonstrate that skin migration can persist after resolution of local skin infection and, surprisingly, the cytokine environment within this nonlymphoid tissue shapes the differentiation state and persistence of the central and peripheral memory T cell pool.