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.