Human skin is protected by four functionally and phenotypically discrete populations of resident and recirculating memory T cells

Four different T cell populations with different functions and migration patterns protect human skin. T cells are more than skin deep Skin is more than just a passive barrier to infection—it’s a dynamic immune microenvironment. Indeed, skin in a human adult is home to around 20 billion memory T cells; however, little is known about the composition and function of these cells. Now, Watanabe et al. characterize four different populations of T cells in the skin, two resident and two recirculating. The resident memory T cells had more potent effector functions than recirculating cells as well as different proliferative capacities. In addition, the recirculating cells returned to the skin at different rates. These data suggest that the different T cell populations in the skin may each provide a singular function in protecting the body from infection. The skin of an adult human contains about 20 billion memory T cells. Epithelial barrier tissues are infiltrated by a combination of resident and recirculating T cells in mice, but the relative proportions and functional activities of resident versus recirculating T cells have not been evaluated in human skin. We discriminated resident from recirculating T cells in human-engrafted mice and lymphoma patients using alemtuzumab, a medication that depletes recirculating T cells from skin, and then analyzed these T cell populations in healthy human skin. All nonrecirculating resident memory T cells (TRM) expressed CD69, but most were CD4+, CD103−, and located in the dermis, in contrast to studies in mice. Both CD4+ and CD8+ CD103+ TRM were enriched in the epidermis, had potent effector functions, and had a limited proliferative capacity compared to CD103− TRM. TRM of both types had more potent effector functions than recirculating T cells. We observed two distinct populations of recirculating T cells, CCR7+/L-selectin+ central memory T cells (TCM) and CCR7+/L-selectin− T cells, which we term migratory memory T cells (TMM). Circulating skin-tropic TMM were intermediate in cytokine production between TCM and effector memory T cells. In patients with cutaneous T cell lymphoma, malignant TCM and TMM induced distinct inflammatory skin lesions, and TMM were depleted more slowly from skin after alemtuzumab, suggesting that TMM may recirculate more slowly. In summary, human skin is protected by four functionally distinct populations of T cells, two resident and two recirculating, with differing territories of migration and distinct functional activities.