Cutaneous T cells promote distinct transcriptional programs in human skin structural cells associated with inflammatory disease

T cells coordinate with structural cells in the skin to promote appropriate inflammatory responses and subsequent restoration of barrier integrity following insult. Single cell studies of human skin have defined an assortment of transcriptionally distinct structural cell populations in healthy tissue and identified inflammatory disease-associated changes in epithelial keratinocytes and dermal fibroblasts. Cutaneous T lymphocyte activity is implicated in the development of inflammatory skin disease, but the mechanisms by which T cells promote disease-associated changes in the skin remain unclear. We show that distinct subsets of circulating and resident CD4+ cutaneous T cells promote a diverse array of transcriptional outcomes in human keratinocytes and fibroblasts. Using these in vitro generated transcriptional signatures, we identify T cell-dependent gene modules associated with inflammatory skin diseases in vivo, such as a set of Thelper17 cell-induced genes in keratinocytes that are enriched in the skin of patients with psoriasis and normalized in response to anti-IL-17 therapy. Thus, we present an approach to define the immune-dependent gene networks of skin structural cells, which we use to study the T cell contribution to inflammatory skin disease and response to anti-cytokine therapy.