Human CD4 + CD103 + cutaneous resident memory T cells are found in the circulation of healthy individuals

Tissue-resident memory T cells (T_RM) persist locally in nonlymphoid tissues where they provide frontline defense against recurring insults. T_RM at barrier surfaces express the markers CD103 and/or CD69, which function to retain them in epithelial tissues. In humans, neither the long-term migratory behavior of T_RM nor their ability to reenter the circulation and potentially migrate to distant tissue sites has been investigated. Using tissue explant cultures, we found that CD4⁺CD69⁺CD103⁺ T_RM in human skin can down-regulate CD69 and exit the tissue. In addition, we identified a skin-tropic CD4⁺CD69^-CD103⁺ population in human lymph and blood that is transcriptionally, functionally, and clonally related to the CD4⁺CD69⁺CD103⁺ T_RM population in the skin. Using a skin xenograft model, we confirmed that a fraction of the human cutaneous CD4⁺CD103⁺ T_RM population can reenter circulation and migrate to secondary human skin sites where they reassume a T_RM phenotype. Thus, our data challenge current concepts regarding the strict tissue compartmentalization of CD4⁺ T cell memory in humans.