Single-cell RNA sequencing of psoriatic skin identifies pathogenic Tc17 cell subsets and reveals distinctions between CD8⁺ T cells in autoimmunity and cancer.

Abstract

Psoriasis is an inflammatory, IL-17-driven skin disease in which autoantigen-induced CD8⁺ T cells have been identified as pathogenic drivers. Our study focused on comprehensively characterizing the phenotypic variation of CD8⁺ T cells in psoriatic lesions. We used single-cell RNA sequencing to compare CD8⁺ T-cell transcriptomic heterogeneity between psoriatic and healthy skin. We identified 11 transcriptionally diverse CD8⁺ T-cell subsets in psoriatic and healthy skin. Among several inflammatory subsets enriched in psoriatic skin, we observed 2 Tc17 cell subsets that were metabolically divergent, were developmentally related, and expressed CXCL13, which we found to be a biomarker of psoriasis severity and which achieved comparable or greater accuracy than IL17A in a support vector machine classifier of psoriasis and healthy transcriptomes. Despite high coinhibitory receptor expression in the Tc17 cell clusters, a comparison of these cells with melanoma-infiltrating CD8⁺ T cells revealed upregulated cytokine, cytolytic, and metabolic transcriptional activity in the psoriatic cells that differed from an exhaustion program. Using high-resolution single-cell profiling in tissue, we have uncovered the diverse landscape of CD8⁺ T cells in psoriatic and healthy skin, including 2 nonexhausted Tc17 cell subsets associated with disease severity.