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

Sci Adv. 2026 Apr 10;12(15):eadw1038. doi: 10.1126/sciadv.adw1038. Epub 2026 Apr 8.

Abstract

Tissue-resident memory T cells (TRM cells) reside in nonlymphoid tissues and provide the first line of defense against pathogens. A subset of TRM cells can egress from nonlymphoid 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 reentered 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 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.

MeSH terms

  • Animals
  • Antigens, CD* / genetics
  • Antigens, CD* / immunology
  • Antigens, CD* / metabolism
  • Antigens, Differentiation, T-Lymphocyte* / genetics
  • Antigens, Differentiation, T-Lymphocyte* / metabolism
  • CD4-Positive T-Lymphocytes* / immunology
  • CD4-Positive T-Lymphocytes* / metabolism
  • CD69 Antigens
  • Epigenesis, Genetic*
  • Genomic Imprinting*
  • Humans
  • Immunologic Memory*
  • Lectins, C-Type* / genetics
  • Lectins, C-Type* / metabolism
  • Memory T Cells* / immunology
  • Memory T Cells* / metabolism
  • Mice
  • Sphingosine-1-Phosphate Receptors / metabolism

Substances

  • Antigens, Differentiation, T-Lymphocyte
  • CD69 Antigens
  • Antigens, CD
  • Lectins, C-Type
  • Sphingosine-1-Phosphate Receptors