Identification of functionally unique CD4 T cells that are the circulating counterparts of epidermal resident memory T cells

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Abstract As a barrier organ, the skin contains specialized T cell populations that combat infection and also help maintain tissue homeostasis and promote wound repair. Circulating skin-tropic T cells can also be identified in the blood based on their expression of the cutaneous lymphocyte antigen (CLA), but the developmental and functional relationships between these circulating CLA+ T cells and tissue-resident T cells in the skin are not fully understood. Using 33-parameter Cytometry by time-of-flight (CyTOF) analysis we identified a novel population of skin-tropic CD4+ T cells in human blood that expresses the CD103 integrin and phenotypically and functionally resembles epidermal resident memory T cells (TRM) in the skin. RNA sequencing identified a set of signature genes shared by circulating CD103+CLAhi T cells in the blood and epidermal TRM cells in the skin, and suggested that CD103+CLAhiT cells contribute to normal skin function and response to tissue damage. Finally, using humanized NSG mice carrying full-thickness human skin grafts we demonstrated that, despite their identification as TRM, CD103+CLAhi T cells in the skin are capable of exiting the tissue and re-entering circulation. Thus, CD103+CLAhi T cells in the blood represent a circulating T cell population of cutaneous TRM, and this provides novel opportunities for the study and therapeutic manipulation of TRM cells in the contexts of cutaneous infection, inflammation, and tissue-repair.