GZMK+CD8+ T cells target a specific acinar cell type in Sjögren's disease
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Le résumé fourni par la source
OBJECTIVES: Sjögren's disease (SjD) is a systemic autoimmune disorder characterized by dysfunction of exocrine glands, particularly the salivary and lacrimal glands, with no clear etiology or effective therapy. This study explores the complex interplay of varied cell types in the salivary glands and their role in the pathology of Sjögren's disease. METHODS: Utilizing single-cell and spatial transcriptomics alongside spatial immunophenotyping to analyze human minor salivary glands, we developed a comprehensive understanding of the cellular landscape of non-SjD salivary glands and how that landscape changes in SjD patients. In vitro cellular assays and novel patient-derived primary epithelial cells were co-cultured with autologous T cells to confirm effector states and the delivery and effect of disease-associated granzymes. RESULTS: We identified previously unrecognized heterogeneity among acinar cells, including a PRR4⁺CST3⁺WFDC2⁻ seromucous acinar population that is selectively lost in Sjögren's disease. Expression and organizational changes were linked to clinical features: (i) T cells in the glands of SSA⁺, high-focus score patients showed increased transcriptional signatures of activation, antigen presentation, and apoptosis resistance compared with patients with mild or moderate disease, and (ii) patients with low immune infiltration exhibited distinct epithelial organization. Notably, GZMK⁺CD8⁺ T cells, which accumulate with disease severity, displayed a cytotoxic transcriptional program, degranulated upon stimulation ex vivo, and localized spatially with immune-engaged epithelial cells. Functional assays demonstrated that GZMK activates interferon signaling in vitro, and autologous co-cultures of patient-derived T cells and epithelial cells validated these findings. CONCLUSIONS: Using single-cell and spatial transcriptomics and proteomics, this study identifies a selective loss of PRR4⁺CST3⁺WFDC2⁻ seromucous acinar cells and a rise in GZMK⁺CD8⁺ T cells in Sjögren's disease, revealing distinct immune-mediated epithelial remodeling and interferon-driven dysfunction across diverse clinical presentations. These findings uncover a novel sub-cytolytic effector mechanism by which GZMK⁺CD8⁺ T cells impair mitochondrial integrity and activate innate immune signaling, linking epithelial injury to type I interferon responses and offering new therapeutic targets.
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Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé ; titre concordant.
- Titre Crossref
- GZMK+CD8+ T cells target a specific acinar cell type in Sjögren's disease
- Date Crossref
- 01/05/2026
- Éditeur
- Elsevier BV
- Type
- journal-article
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
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National Institute of Dental and Craniofacial Research Salivary Disorders Unit pays non établi dans la noticeStructure de recherche
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University of Maryland National Institute of Dental and Craniofacial Research pays non établi dans la noticeUniversité ou école supérieure
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National Institutes of Health pays non établi dans la noticeOrganisme public
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National Cancer Institute pays non établi dans la noticeOrganisme public
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Center for Cancer Research pays non établi dans la noticeStructure de recherche
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Institut de Recherche et d’Innovation pays non établi dans la noticeStructure de recherche
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Virginia Commonwealth University Department of Biostatistics pays non établi dans la noticeUniversité ou école supérieure
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National Institute of Allergy and Infectious Diseases T-lymphocyte Biology Section pays non établi dans la noticeStructure de recherche
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Wellcome Sanger Institute pays non établi dans la noticeOrganisation à but non lucratif
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Michigan Medicine pays non établi dans la noticeÉtablissement de santé
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National Eye Institute Consult Services Section pays non établi dans la noticeStructure de recherche
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National Institute of Arthritis and Musculoskeletal and Skin Diseases pays non établi dans la noticeStructure de recherche
Salivary Disorders Unit — National Institute of Dental and Craniofacial Research, National Institute of Dental and Craniofacial Research — University of Maryland et National Institutes of Health, avec 9 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.