CD69 regulates the tissue dynamics of epigenetically imprinted memory CD4 + T cells

Tissue-resident memory T cells (T RM cells) reside in nonlymphoid tissues and provide the first line of defense against pathogens. A subset of T RM cells can egress from nonlymphoid tissues into the circulation. However, the functional consequences and the extent of epigenetic imprinting in recirculating T RM cells remain unknown. We herein demonstrate that in CD4 + T RM cells, the CD69-S1PR1 axis controls tissue residency and that interrupting this axis results in ablation of lung CD4 + T RM cells. A subpopulation of CD69 + CD4 + T RM cells reentered circulation via lymphatic vessels, where they epigenetically maintained the characteristics of T RM cells in both mice and humans. Circulating Ex-lung-T RM cells in mice caused enhanced skin inflammation compared to circulating memory cells. Furthermore, we identified GPR183 and CD161 as potential markers of Ex-T RM in human peripheral blood mononuclear cells. In chronic inflammatory diseases, the transposition of allergic inflammation to multiple tissues may therefore occur via recirculation of tissue-imprinted memory CD4 + T cells.