Gaydosik Alyxzandria M, Tabib Tracy, Das Jishnu, Larregina Adriana, Lafyatis Robert, Fuschiotti Patrizia
Department of Medicine, Division of Rheumatology and Clinical Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Department of Medicine, Division of Rheumatology and Clinical Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Center for Systems Immunology, Departments of Immunology and Computational & Systems Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Ann Rheum Dis. 2025 May;84(5):798-809. doi: 10.1016/j.ard.2025.01.022. Epub 2025 Feb 1.
To analyse the immune mechanisms of diffuse cutaneous systemic sclerosis (dcSSc) skin disease focusing on CD8 T-cell responses in the affected skin of patients because chronic inflammation, vasculopathy, and extensive cutaneous fibrosis are prominent features of dcSSc skin disease, causing pain and disability in patients, with no effective therapy.
Single-cell transcriptomics and epigenomics were applied to well-characterised patient skin samples to identify transcriptomes and key regulators of skin-resident CD8 T-cell subsets. Multicolor immunofluorescence miscoscopy was used to validate molecular findings. Ex vivo skin explant assays were used to functionally characterise dysfunctional CD8 T-cell subsets on nonlesional autologous skin.
We identified 2 major developmentally connected CD8 T-cell subpopulations that were expanded in SSc skin lesions compared with healthy control skin. The first was a heterogeneous subset of effector-memory CD8KLRB1IL7R cells characterised by increased cytolytic and Tc2/Tc17 effector functions that appear to induce tissue damage and fibrosis in early-stage dcSSc skin lesions. The second, found primarily in patients with late-stage disease, was an exhausted CD8KLRG1IL7R subset that exhibited transcriptional features of long-lived effector cells, likely contributing to chronic inflammation. Significantly, both subsets were also expanded in other benign dermatoses, implicating these cell populations in the pathogenesis of chronic human skin inflammation.
This study provides new insight into core regulatory programmes modulating skin-resident CD8 T-cell plasticity and identifies distinct CD8 T-cell subpopulations that contribute to initiation and chronicity of inflammatory responses in systemic sclerosis skin lesions. These findings reveal prospective molecular targets for new therapeutic strategies against this incurable disease.
分析弥漫性皮肤系统性硬化症（dcSSc）皮肤病的免疫机制，重点关注患者受累皮肤中的CD8 T细胞反应，因为慢性炎症、血管病变和广泛的皮肤纤维化是dcSSc皮肤病的突出特征，导致患者疼痛和残疾，且尚无有效治疗方法。
将单细胞转录组学和表观基因组学应用于特征明确的患者皮肤样本，以识别皮肤驻留CD8 T细胞亚群的转录组和关键调节因子。采用多色免疫荧光显微镜验证分子研究结果。体外皮肤外植体试验用于对非病变自体皮肤上功能失调的CD8 T细胞亚群进行功能表征。
我们鉴定出2个在发育上相关的主要CD8 T细胞亚群，与健康对照皮肤相比，它们在SSc皮肤病变中扩增。第一个是效应记忆CD8KLRB1IL7R细胞的异质性亚群，其特征是细胞溶解和Tc2/Tc17效应功能增加，似乎在早期dcSSc皮肤病变中诱导组织损伤和纤维化。第二个主要在疾病晚期患者中发现，是一个耗竭的CD8KLRG1IL7R亚群，表现出长寿效应细胞的转录特征，可能导致慢性炎症。值得注意的是，这两个亚群在其他良性皮肤病中也有扩增，提示这些细胞群体参与了慢性人类皮肤炎症的发病机制。
本研究为调节皮肤驻留CD8 T细胞可塑性的核心调控程序提供了新见解，并鉴定出不同的CD8 T细胞亚群，它们有助于系统性硬化症皮肤病变中炎症反应的起始和慢性化。这些发现揭示了针对这种不治之症的新治疗策略的潜在分子靶点。
