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

Background: Psoriasis is an inflammatory, IL-17-driven skin disease in which autoantigen-induced CD8(+) T cells have been identified as pathogenic drivers. Objective: Our study focused on comprehensively characterizing the phenotypic variation of CD8(+) T cells in psoriatic lesions. Methods: We used single-cell RNA sequencing to compare CD8(+) T-cell transcriptomic heterogeneity between psoriatic and healthy skin. Results: 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. Conclusion: 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.

Automated summary

This study utilized single-cell RNA sequencing to compare the transcriptomic heterogeneity of CD8(+) T cells in psoriatic and healthy skin, identifying several inflammatory subsets enriched in psoriatic skin and two Tc17 cell subsets associated with disease severity. Despite high expression of coinhibitory receptors, the psoriatic Tc17 cells exhibited upregulated cytokine, cytolytic, and metabolic activity, distinguishing them from an exhaustion program observed in melanoma-infiltrating CD8(+) T cells.