Cutaneous T cells promote distinct cellular outcomes in human keratinocytes and fibroblasts

Abstract

Abstract Human skin is a barrier tissue home to a highly specialized immune environment in which leukocytes coordinate with local epithelial and stromal tissue in response to physical, chemical, and biological stresses. T cells are abundant in the skin and are required for both host defense to pathogens and the subsequent repair of damaged tissue. Cutaneous lymphocytes include both resident and migratory fractions, which can be identified and isolated using expression of the cutaneous lymphocyte antigen (CLA). There are multiple subsets of CLA+ T cells, each having a distinct phenotype and functional capacity, however their precise roles in contributing to host-protective and tissue-repair responses remains incompletely understood. We assessed the function of eight different CD4+CLA+ cutaneous T cell subsets from the skin and blood, including traditional T helper lineages and a novel subset of CD4+CLA+CD103+ T cells with a tissue repair phenotype, by bulk RNAseq analysis of keratinocytes and fibroblasts following administration of activated T cell supernatants. Differential gene expression and pathway analysis reveal distinct cellular outcomes in keratinocytes and fibroblasts that depend strongly on T cell source and the activity of specific cytokines. Our findings define a diverse array of immune-induced states in the skin that are dependent on the unique functional capacity of various T cell subsets, thereby constructing a comprehensive tool to map how cutaneous T cells contribute to pathological disruption, tissue repair and return to homeostasis within human skin.