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

Abstract

Abstract The skin is an immunologically active barrier tissue specialized to deal with a litany of external stresses. Immune cells coordinate with structural cells in the skin to promote appropriate inflammatory responses and subsequent restoration of barrier integrity following insult. Recent single cell analyses of human skin have defined previously unappreciated transcriptional heterogeneity in structural cells, including disease-associated changes in keratinocytes and fibroblasts. Cutaneous T cell 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 now show that distinct subsets of circulating and resident CD4 +cutaneous T cells promote a diverse array of cytokine-dependent transcriptional outcomes in human keratinocytes and fibroblasts. We used these in vitro generated transcriptional signatures to identify T cell-dependent gene modules associated with inflammatory skin disease in vivo. For example, we find that T helper17 cells regulate the expression of epigenetic modifiers in keratinocytes, genes that are enriched in the skin of patients with psoriasis and normalized in response to anti-IL-17 therapy. Thus, we have identified T cell-dependent cytokine-driven transcriptional changes associated with inflammatory skin disease that can be used to dissect immune mechanisms of anti-cytokine therapeutic activity.