Abstract: SA-PO0746
Granzyme K-Expressing CD8+ T Cells Drive Complement Activation and Tissue Damage in ANCA-Associated Glomerulonephritis
Session Information
- Glomerular Diseases: Profiling Through Multiomics
November 08, 2025 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1401 Glomerular Diseases: Mechanisms, including Podocyte Biology
Authors
- Panzer, Ulf, Universitatsklinikum Hamburg-Eppendorf, Hamburg, Germany
- Asada, Nariaki, Universitatsklinikum Hamburg-Eppendorf, Hamburg, Germany
- Wang, Huiying, Universitatsklinikum Hamburg-Eppendorf, Hamburg, Germany
- Sultana, Zeba, Universitatsklinikum Hamburg-Eppendorf, Hamburg, Germany
- Khatri, Robin, Universitatsklinikum Hamburg-Eppendorf, Hamburg, Germany
- Hellmig, Malte, Universitatsklinikum Hamburg-Eppendorf, Hamburg, Germany
- Engesser, Jonas, Universitatsklinikum Hamburg-Eppendorf, Hamburg, Germany
- Ginsberg, Pauline, Universitatsklinikum Hamburg-Eppendorf, Hamburg, Germany
- Paust, Hans-Joachim, Universitatsklinikum Hamburg-Eppendorf, Hamburg, Germany
- Kaffke, Anna, Universitatsklinikum Hamburg-Eppendorf, Hamburg, Germany
- Peters, Anett, Universitatsklinikum Hamburg-Eppendorf, Hamburg, Germany
- Bonn, Stefan, Universitatsklinikum Hamburg-Eppendorf, Hamburg, Germany
- Huber, Tobias B., Universitatsklinikum Hamburg-Eppendorf, Hamburg, Germany
- Freiwald, Tilo, Universitatsklinikum Hamburg-Eppendorf, Hamburg, Germany
- Zipfel, Peter F., Leibniz-Institut fur Naturstoff-Forschung und Infektionsbiologie eV Hans-Knoll-Institut, Jena, Thuringia, Germany
- Wiech, Thorsten, Universitatsklinikum Hamburg-Eppendorf, Hamburg, Germany
- Mittrücker, Hans-willi, Universitatsklinikum Hamburg-Eppendorf, Hamburg, Germany
- Krebs, Christian F., Universitatsklinikum Hamburg-Eppendorf, Hamburg, Germany
Background
ANCA–associated vasculitis is a systemic autoimmune disease and the most common cause of rapidly progressive GN (ANCA-GN). Recent experimental and clinical studies highlight the critical role of the complement system in the pathogenesis of ANCA-GN, but the underlying molecular mechanisms driving complement activation are unclear. Two recent Nature publications (PMID 39914456, PMID 38826230) discovered a new mechanism of complement activation that is driven exclusively by granzyme K (GZMK), a serine protease that is mainly expressed by T cells. In this study, we aim to decipher the potential role of this pathway in ANCA-GN.
Methods
Here we applied combined single-cell RNA-sequencing and spatial transcriptomic technologies to blood and kidney biopsy samples of 92 ANCA-GN patients and 16 healthy controls. In total 82 thousand T cells were isolated from kidney biopsies of ANCA-GN patients for single-cell RNA+TCR sequencing, and more than 3 million immune and kidney cells were analyzed by high-resolution spatial transcriptomics. In addition, ex vivo T cell activation and complement activation assays were performed.
Results
Using this immune profiling approach, we identified a distinct CD8+ T cell population, characterized by the expression of GZMK, as the main cellular source of GZMK in ANCA-GN patients. These GZMK+ CD8+ T cells were clonally expanded, highly activated and enriched in the kidney. In an independent spatial transcriptomic validation cohort (48 ANCA-GN patients), we confirmed that GZMK+ CD8+ T cells were increased in patients with ANCA-GN and showed that GZMK producing CD8+ T cells are localized in renal areas of complement activation and tissue injury. Using in vitro assays, we finally showed that kidney CD8+ from ANCA-GN patients release GZMK protein upon T cell receptor activation, and that GZMK directly induces complement activation and deposition on the surface of target cells.
Conclusion
These findings decode a previously unidentified mechanism of complement activation in the kidney of patients with ANCA-GN, and identify the CD8+ GZMK+ T cell-mediated pathway as an attractive therapeutic target for the treatment of these patients.
Funding
- Government Support – Non-U.S.