GZMK+CD8+ T cells target a specific acinar cell type in Sjögren's disease

作者：Thomas Pranzatelli, Paola Pérez, Anson T. Ku, Bruno Fernandes Matuck, Khoa Huynh, Shunsuke Sakai, Mehdi Abed, Shyh-Ing Jang, Eiko Yamada, Kalie Dominick, Zara Ahmed, Amanda J. Oliver, Rachael Bogle, Quinn T. Easter, Alan N. Baer, Eileen Pelayo, Zohreh Khavandgar, David E. Kleiner, M. Teresa Magone, Sarthak Gupta, Christopher J. Lessard, A. Darise Farris, Peter D. Burbelo, Daniel Martı́n, Robert J. Morell, Changyu Zheng, Nicholas Rachmaninoff, Jose Maldonado-Ortiz, Katarzyna M. Tyc, Xufeng Qu, Marit H. Aure, M Dezfulian, Ross Lake, Sarah A. Teichmann, Daniel L. Barber, Lam C. Tsoi, Adam G. Sowalsky, Jinze Liu, Jóhann E. Guðjónsson, Kevin M. Byrd, Philip L. Johnson, John A. Chiorini, Blake M. Warner · 发表于：Annals of the Rheumatic Diseases · 年份：2025 · DOI：10.1016/j.ard.2025.08.014 · 被引用次数：14 · 研究领域：Salivary Gland Disorders and Functions、T-cell and B-cell Immunology、Cancer Immunotherapy and Biomarkers

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 trans...