A novel humanized mouse model to study the function of human cutaneous memory T cells in vivo in human skin

Human skin contains a population of memory T cells that support tissue homeostasis and provide protective immunity. T cell function in human skin is difficult to study due to a lack of adequate in vivo models. Thus, we utilized immunodeficient NOD-scid IL2rγnull (NSG) mice that carried in vivo-generated engineered skin (ES) and received adoptively transferred human peripheral blood mononuclear cells to follow the migration and function of circulating human memory T cells in human ES in vivo. ES were generated from human keratinocytes and fibroblasts only and initially contained no skin-resident immune cells. This reductionist system allowed us to study human T cell recruitment into non-inflamed and non-infected human skin, reflecting physiological skin conditions. Circulating human memory T cells preferentially infiltrated the human ES and these had the diverse functional profiles of T cells found in fresh human skin. Importantly, the chemokine and cytokine microenvironment found in the ES closely resembled that of non-inflamed human skin, which supports T cell maintenance and function. Upon entering the ES T cells assumed a resident memory T cell-like phenotype in the absence of infection and these cutaneous T cells were activated locally upon injection of Candida albicans that was presented by autologous monocyte derived dendritic cells within the human ES. In summary, we have generated a novel mouse model with broad utility in studies of the dynamics of human cutaneous memory T cell generation, antigen-specific memory T cell responses, and the role of the skin microenvironment to skin immunity in vivo.