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

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 (T-RM) expressed CD69, but most were CD4(+), CD103(-), and located in the dermis, in contrast to studies in mice. Both CD4(+) and CD8(+) CD103(+) T-RM were enriched in the epidermis, had potent effector functions, and had a limited proliferative capacity compared to CD103(-) T-RM. T-RM 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 (T-CM) and CCR7(+)/L-selectin(-) T cells, which we term migratory memory T cells (T-MM). Circulating skin-tropic T-MM were intermediate in cytokine production between T-CM and effector memory T cells. In patients with cutaneous T cell lymphoma, malignant T-CM and T-MM induced distinct inflammatory skin lesions, and T-MM were depleted more slowly from skin after alemtuzumab, suggesting that T-MM 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.