Th105 - T Cell-Dependent Gene Programs in Keratinocytes and Dermal Fibroblasts Are Associated with Inflammatory and Fibrotic Skin Disease

Hannah DeBerg – Benaroya Research Institute; Mitch Fahning – Benaroya Research Institute; Matthew Dufort – Benaroya Research Institute; Suraj Varkhande – University of Salzburg; Iris Gratz – University of Salzburg; Daniel Campbell – Benaroya Research Institute

Abstract Text: The skin is an immunologically active tissue specialized to deal with a litany of stresses. Skin immune and structural cells coordinate to promote appropriate inflammatory responses and subsequent restoration of barrier integrity after insult. Single cell analyses of human skin show an array of structural cell gene programs, including disease-associated changes in keratinocytes and fibroblasts. T cell activity is implicated in many inflammatory skin diseases, but the mechanisms T cell use to promote disease-associated changes is understudied. We use 2D culture and a novel 3D organotypic skin model to demonstrate how distinct subsets of cutaneous CD4+ T cells promote diverse transcriptional outcomes in keratinocytes and fibroblasts. We use these in vitro generated transcriptional signatures to identify T cell-dependent gene modules associated with inflammatory skin disease in vivo. We define a set of Th17 cell-induced genes in keratinocytes, including epigenetic modifiers, that are enriched in psoriasis patient skin and normalized in response to anti-IL-17 therapy. We also describe T cell-dependent gene programs that are enriched in scleroderma-associated fibroblasts important for fibrotic disease progression and track these populations in patient skin by spatial transcriptomic analysis. Thus, we have identified novel T cell-dependent gene programs of healthy skin that we use to explore the immune perturbations of inflammatory disease and interventional therapies.