Cutaneous CD4+T cell subsets promote distinct outcomes in human keratinocytes and fibroblasts

Abstract Epithelial, stromal, and immune cells in the skin cooperate to ensure appropriate response to pathogens and environmental damage. Recent single cell transcriptional analyses of healthy and fibrotic human skin revealed a wide range of phenotypes that arise in response to distinct cytokine milieu. Cutaneous T cells promote host defense and the subsequent resolution of inflammation and repair of damaged skin through the production of cytokines, but the precise mechanisms T cells use to impact the differentiation and function of skin cells involved in inflammatory and tissue-repair responses remain understudied. To assess the functional capacity of cutaneous lymphocytes we isolated skin-tropic and skin-resident T helper cells including a novel population of pro-fibrotic migratory tissue resident memory cells we recently discovered. We measured both quantitative T cell cytokine production following TCR stimulation, and the impact of T cell derived cytokines on human keratinocyte and fibroblast transcriptional profile and morphology. We find that phenotypically and functionally distinct circulating and skin-resident T cell subsets have the capacity to promote discrete cytokine-dependent transcriptional and cellular outcomes in the skin including the induction of metabolic, proliferative, and inflammatory gene profiles. Thus, cutaneous T cells support host-protective and tissue-repair responses through direct activity on keratinocytes and dermal fibroblasts.