Single-cell RNA sequencing of psoriatic skin identifies pathogenic Tc17 cell subsets and reveals distinctions between CD8 T cells in autoimmunity and cancer.
The Journal of allergy and clinical immunology
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.
10.1016/j.jaci.2020.11.028
The IL-17A-producing CD8+ T-cell population in psoriatic lesional skin comprises mucosa-associated invariant T cells and conventional T cells.
The Journal of investigative dermatology
IL-17A is pivotal in the etiology of psoriasis, and CD8(+) T cells with the ability to produce this cytokine (Tc17 cells) are over-represented in psoriatic lesions. Here we demonstrate that the frequency of Tc17 cells in peripheral blood of psoriasis patients correlated with the clinical severity of the disease. Analysis of cutaneous-associated lymphocyte antigen expression showed that the blood Tc17 population contains a significantly higher proportion of cells with skin-homing potential compared with the CD8(+) T-cell population lacking IL-17A/IL-22 expression. IL-17A-producing CD8(+) T cells in blood have previously been reported to belong mainly to the mucosa-associated invariant T-cell (MAIT cell) lineage characterized by TCR Vα7.2 chain, CD161, IL-18Rα, and multidrug transporter ABCB1 expression. We demonstrate the presence of CD8(+) MAIT cells in the dermis and epidermis of psoriatic plaques, as well as healthy skin; however, IL-17A-producing CD8(+) MAIT cells were predominantly found in psoriatic skin. Notably, we observed IL-17A production in a large proportion of psoriatic plaque-derived CD8(+) T cells devoid of MAIT cell characteristics, likely representing conventional CD8(+) T cells. In conclusion, we provide supporting evidence that implicates Tc17 cells in the pathogenesis of psoriasis and describe the presence of innate CD8(+) MAIT cells in psoriatic lesions as an alternative source of IL-17A.
10.1038/jid.2014.261
The Inflammatory Response in Psoriasis: a Comprehensive Review.
Deng Yaxiong,Chang Christopher,Lu Qianjin
Clinical reviews in allergy & immunology
Psoriasis is a chronic inflammatory autoimmune disease characterized by an excessively aberrant hyperproliferation of keratinocytes. The pathogenesis of psoriasis is complex and the exact mechanism remains elusive. However, psoriasis is thought to result from a combination of genetic, epigenetic, and environmental influences. Recent studies have identified that epigenetic factors including dysregulated DNA methylation levels, abnormal histone modification and microRNAs expressions are involved in the development of psoriasis. The interplay of immune cells and cytokines is another critical factor in the pathogenesis of psoriasis. These factors or pathways include Th1/Th2 homeostasis, the Th17/Treg balance and the IL-23/Th17 axis. Th17 is believed particularly important in psoriasis due to its pro-inflammatory effects and its involvement in an integrated inflammatory loop with dendritic cells and keratinocytes, contributing to an overproduction of antimicrobial peptides, inflammatory cytokines, and chemokines that leads to amplification of the immune response. In addition, other pathways and signaling molecules have been found to be involved, including Th9, Th22, regulatory T cells, γδ T cells, CD8(+) T cells, and their related cytokines. Understanding the pathogenesis of psoriasis will allow us to develop increasingly efficient targeted treatment by blocking relevant inflammatory signaling pathways and molecules. There is no cure for psoriasis at the present time, and much of the treatment involves managing the symptoms. The biologics, while lacking the adverse effects associated with some of the traditional medications such as corticosteroids and methotrexate, have their own set of side effects, which may include reactivation of latent infections. Significant challenges remain in developing safe and efficacious novel targeted therapies that depend on a better understanding of the immunological dysfunction in psoriasis.
10.1007/s12016-016-8535-x
Navigating the diverse immune landscapes of psoriatic arthritis.
Seminars in immunopathology
The goal of remission in psoriatic arthritis (PsA) has remained elusive despite the influx of a range of new therapies over the last 20 years. In contrast, therapeutic responses to agents that inhibit IL-23 or IL-17 have demonstrated impressive efficacy in psoriasis. In part, the divergent responses in these two disorders are likely related to the heterogeneity of tissue involvement in PsA and the interplay of multiple different cell populations and molecular pathways. In this narrative review, we will examine the plasticity of the immune response in PsA from the perspective of the Th17 cell and monocyte and discuss recent findings regarding the importance of CD8+ T resident cells in disease pathogenesis. We will then examine the effects of cytokines on epithelial cell and stromal populations and finally discuss new data regarding immune cell and tissue resident cell cross-talk in entheses and bone. Lastly, the potential therapeutic targets that have emerged from these investigations will be discussed.
10.1007/s00281-021-00848-x
Activation of CD8 T cells accelerates anti-PD-1 antibody-induced psoriasis-like dermatitis through IL-6.
Tanaka Ryota,Ichimura Yuki,Kubota Noriko,Saito Akimasa,Nakamura Yoshiyuki,Ishitsuka Yosuke,Watanabe Rei,Fujisawa Yasuhiro,Kanzaki Mirei,Mizuno Seiya,Takahashi Satoru,Fujimoto Manabu,Okiyama Naoko
Communications biology
Use of immune checkpoint inhibitors that target programmed cell death-1 (PD-1) can lead to various autoimmune-related adverse events (irAEs) including psoriasis-like dermatitis. Our observations on human samples indicated enhanced epidermal infiltration of CD8 T cells, and the pathogenesis of which appears to be dependent on IL-6 in the PD-1 signal blockade-induced psoriasis-like dermatitis. By using a murine model of imiquimod-induced psoriasis-like dermatitis, we further demonstrated that PD-1 deficiency accelerates skin inflammation with activated cytotoxic CD8 T cells into the epidermis, which engage in pathogenic cross-talk with keratinocytes resulting in production of IL-6. Moreover, genetically modified mice lacking PD-1 expression only on CD8 T cells developed accelerated dermatitis, moreover, blockade of IL-6 signaling by anti-IL-6 receptor antibody could ameliorate the dermatitis. Collectively, PD-1 signal blockade-induced psoriasis-like dermatitis is mediated by PD-1 signaling on CD8 T cells, and furthermore, IL-6 is likely to be a therapeutic target for the dermatitis.
10.1038/s42003-020-01308-2
Psoriasis Pathogenesis and Treatment.
Rendon Adriana,Schäkel Knut
International journal of molecular sciences
Research on psoriasis pathogenesis has largely increased knowledge on skin biology in general. In the past 15 years, breakthroughs in the understanding of the pathogenesis of psoriasis have been translated into targeted and highly effective therapies providing fundamental insights into the pathogenesis of chronic inflammatory diseases with a dominant IL-23/Th17 axis. This review discusses the mechanisms involved in the initiation and development of the disease, as well as the therapeutic options that have arisen from the dissection of the inflammatory psoriatic pathways. Our discussion begins by addressing the inflammatory pathways and key cell types initiating and perpetuating psoriatic inflammation. Next, we describe the role of genetics, associated epigenetic mechanisms, and the interaction of the skin flora in the pathophysiology of psoriasis. Finally, we include a comprehensive review of well-established widely available therapies and novel targeted drugs.
10.3390/ijms20061475