CD1a-autoreactive T cell sensing of skin barrier compromise.

BACKGROUND: T cells are often enriched at barrier tissues, yet little is known of their roles in barrier sensing and relevance to associated disease. CD1a is a Major Histocompatibility Complex class I-like molecule expressed by Langerhans cells, which forms complexes with lipid antigens to facilitate recognition by non-classical CD1a-reactive T cells. OBJECTIVES: Langerhans cells are altered in lesional atopic dermatitis (AD) skin, but the role of CD1a in disease pathogenesis has not been extensively investigated. METHODS: Human skin challenge, single cell and spatial transcriptomic based approaches and functional immunology were used to assess the role of CD1a in AD pathogenesis. RESULTS: Skin allergen challenge in individuals with AD induced skin CCL17 and CCL22 concentrations that promoted CCR4+ T cell migration. Single cell resolution proteo-transcriptomics from human lesional AD skin tissue identified a dominant CCL17/22 source as a persistent population of activated skin CD1a+ dendritic cells (DCs) previously shown to be transiently enriched in human skin wounds. Single-cell resolution spatial tissue analyses showed that these cells were predominantly located within lesional sub-epidermal microcompartment clusters co-localising with distinct subpopulations of Th2 cells. Activated skin DCs expressed neutral sphingomyelinase, which processed inhibitory long chain sphingomyelin to drive Th2 cell CD1a-autoreactivity. CONCLUSIONS: In summary, the findings are consistent with human CD1a-autoreactive T cells sensing of chronic skin barrier compromise through detection of altered sphingomyelin cycle activity, with implications for the pathogenesis of atopic and related disease.