Dataset Information

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

ABSTRACT:

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.

SUBMITTER: Liu J

PROVIDER: S-EPMC9179181 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

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Publications

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

Liu Jared J Chang Hsin-Wen HW Huang Zhi-Ming ZM Nakamura Mio M Sekhon Sahil S Ahn Richard R Munoz-Sandoval Priscila P Bhattarai Shrishti S Beck Kristen M KM Sanchez Isabelle M IM Yang Eric E Pauli Mariela M Arron Sarah T ST Fung-Leung Wai-Ping WP Munoz Ernesto E Liu Xuejun X Bhutani Tina T North Jeffrey J Fourie Anne M AM Rosenblum Michael D MD Liao Wilson W

The Journal of allergy and clinical immunology 20201209 6

<h4>Background</h4>Psoriasis is an inflammatory, IL-17-driven skin disease in which autoantigen-induced CD8<sup>+</sup> T cells have been identified as pathogenic drivers.<h4>Objective</h4>Our study focused on comprehensively characterizing the phenotypic variation of CD8<sup>+</sup> T cells in psoriatic lesions.<h4>Methods</h4>We used single-cell RNA sequencing to compare CD8<sup>+</sup> T-cell transcriptomic heterogeneity between psoriatic and healthy skin.<h4>Results</h4>We identified 11 tran ...[more]

PMID: 33309739

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Project description:Conventional immunosuppressants cause side effects and do not prevent the recurrence of autoimmune diseases. Moreover, they may not inhibit autoimmunity mediated by pathogenic memory T-cells. Dihydroartemisinin (DHA) has been shown to regulate autoimmunity. However, it remains unknown whether DHA impacts psoriasis and its recurrence. The objective of this study was to determine therapeutic effects of DHA on psoriasis and its relapse as well as its underlying mechanisms. Methods: We established animal models of imiquimod (IMQ)-induced psoriasis-like wild-type mice and humanized NSG mice receiving lesional human skin from patients with psoriasis. Many immunoassays, including immunohistochemistry, flow cytometry, quantitative RT-PCR and Western blotting, were performed. Results: We found that DHA not only ameliorated acute skin lesion of psoriatic mice, but also alleviated its recurrence by diminishing CD8+ central memory T (TCM) and CD8+ resident memory T (TRM) cells. It attenuated epidermal pathology and T-cell infiltration in the skin of IMQ-induced psoriatic mice while suppressing expression of IL-15, IL-17 and other proinflammatory cytokines in the skin. Surprisingly, DHA reduced the frequency and number of CD8+, but not CD4+, subset of CD44highCD62Lhigh TCM in psoriatic mice, whereas methotrexate (MTX) lowered CD4+, but not CD8+, TCM frequency and number. Indeed, DHA, but not MTX, downregulated eomesodermin (EOMES) and BCL-6 expression in CD8+ T-cells. Furthermore, DHA, but not MTX, reduced the presence of CD8+CLA+, CD8+CD69+ or CD8+CD103+ TRM cells in mouse skin. Interestingly, treatment with DHA, but not MTX, during the first onset of psoriasis largely prevented psoriasis relapse induced by low doses of IMQ two weeks later. Administration of recombinant IL-15 or CD8+, but not CD4+, TCM cells resulted in complete recurrence of psoriasis in mice previously treated with DHA. Finally, we demonstrated that DHA alleviated psoriatic human skin lesions in humanized NSG mice grafted with lesional skin from psoriatic patients while reducing human CD8+ TCM and CD103+ TRM cells in humanized mice. Conclusion: We have provided the first evidence that DHA is advantageous over MTX in preventing psoriasis relapse by reducing memory CD8+ T-cells.

Dataset Information

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

Background

Objective

Methods

Results

Conclusion

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

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

Background

Objective

Methods

Results

Conclusion

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

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