T Cells Promote Distinct Transcriptional Programs of Cutaneous Inflammatory Disease in Keratinocytes and Dermal...

T cells and structural cells coordinate appropriate inflammatory responses and restoration of barrier integrity following insult. Dysfunctional T cells precipitate skin pathology occurring alongside altered structural cell frequencies and transcriptional states, but to what extent different T cells promote disease-associated changes remains unclear. We show that functionally diverse circulating and skin-resident CD4⁺CLA⁺ T-cell populations promote distinct transcriptional outcomes in human keratinocytes and fibroblasts associated with inflamed or healthy tissue. We identify T helper 17 cell-induced genes in keratinocytes that are enriched in psoriasis patient skin and normalized by anti-IL-17 therapy. We also describe a CD103⁺ skin-resident T-cell-induced transcriptional module enriched in healthy controls that is diminished during psoriasis and scleroderma and show that CD103⁺ T-cell frequencies are altered during disease. Interrogating clinical data using immune-dependent transcriptional signatures defines the T-cell subsets and genes distinguishing inflamed from healthy skin and allows investigation of heterogeneous patient responses to biologic therapy.