CD69 regulates the tissue dynamics of epigenetically imprinted memory CD4+ T cells [RNA-seq_ATAC-seq]

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