Rui Hirasawa, Chiaki Iwamura, Masahiro Kiuchi, Takahisa Hishiya, Atsushi Sasaki, Kohei Kakinuma, Kanae Ohishi, Akane Kurosugi, Masahiro Nemoto, Kota Kokubo, Takuto Hiramoto, Tomohisa Iinuma, Syuji Yonekura, Atsushi Onodera, Motoko Y. Kimura, SHINICHIRO MOTOHASHI, Damon J. Tumes, Toyoyuki Hanazawa, Toshinori Nakayama, Seiji Ohtori, Kiyoshi Hirahara
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.