T cell-dependent regulation of dermal fibroblast gene programs in healthy human tissue is lost during inflammatory skin disease 3395

Description Human skin immune and structural cells coordinate the inflammatory response and wound healing following insult. Dysregulated T cell activity is implicated in the development of inflammatory skin disease and correlates with changes to structural cell populations, but the mechanisms T cells use to maintain healthy skin function remain understudied. Using 2D culture and 3D organotypic skin we demonstrate that distinct subsets of cutaneous CD4+ T cells promote diverse transcriptional outcomes in dermal fibroblasts. We find that fibroblasts are enriched in T cell-dependent genes in healthy skin but that this is diminished in psoriasis and scleroderma patient skin. LGR5-fibroblasts, a population associated with healthy dermis and greatly reduced in scleroderma, has a transcriptional program enriched in skin-resident CD4+CD103+ T cell-dependent genes. Using spatial transcriptomics and flow cytometry we show that skin CD4+CD103+ T cells are reduced in scleroderma. A migratory fraction of this population in the blood is also reduced in scleroderma and psoriasis subjects. These data suggest CD4+CD103+ T cells are required to maintain healthy skin-associated gene programs including of LGR5-fibroblasts, and that loss of these T cells corresponds with the development of disease. Promoting healthy skin T cell-dependent gene programs represents an attractive avenue for therapies aimed at reversing immune-driven perturbations of inflammatory disease and restoring normal fibroblast function. Funding Sources This work was supported by a New Investigator research award (National Scleroderma Foundation) and R21AI185642 (NIAID, NIH) to PAM, R01AI127726 to IKG and DJC (NIAID, NIH), and R01AI169893 to HAD, IKG and DJC (NIAID, NIH).