Transcriptional and Clonal Characterization of Cytotoxic T Cells in Crescentic Glomerulonephritis

• Published in: Journal of the American Society of Nephrology 2023-06, Vol.34 (6), p.1003-1018
• Main Authors: Mueller, Anne, Zhao, Yu, Cicek, Hakan, Paust, Hans-Joachim, Sivayoganathan, Amirrtavarshni, Linke, Alexandra, Wegscheid, Claudia, Wiech, Thorsten, Huber, Tobias B, Meyer-Schwesinger, Catherine, Bonn, Stefan, Prinz, Immo, Panzer, Ulf, Tiegs, Gisa, Krebs, Christian F, Neumann, Katrin
• Format: Article
• Language: English
• Subjects: Acute Disease; Animals; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis - complications; Antibodies, Antineutrophil Cytoplasmic; Caspase 3; Glomerulonephritis; Glomerulonephritis, Membranoproliferative - complications; Granzymes; Mice; T-Lymphocytes, Cytotoxic - metabolism; T-Lymphocytes, Cytotoxic - pathology
• ISSN: 1046-6673; 1533-3450
• DOI: 10.1681/ASN.0000000000000116

T-cell infiltration is a hallmark of crescentic GN (cGN), often caused by ANCA-associated vasculitis. Pathogenic T-cell subsets, their clonality, and downstream effector mechanisms leading to kidney injury remain to be fully elucidated. Single-cell RNA sequencing and T-cell receptor sequencing revealed activated, clonally expanded cytotoxic CD4 + and CD8 + T cells in kidneys from patients with ANCA-associated cGN. In experimental cGN, kidney-infiltrating CD8 + T cells expressed the cytotoxic molecule, granzyme B (GzmB), which induced apoptosis in renal tissue cells by activation of procaspase-3, and aggravated disease pathology. These findings describe a pathogenic function of (clonally expanded) cytotoxic T cells in cGN and identify GzmB as a mediator and potential therapeutic target in immune-mediated kidney disease. Crescentic GN (cGN) is an aggressive form of immune-mediated kidney disease that is an important cause of end stage renal failure. Antineutrophilic cytoplasmic antibody (ANCA)-associated vasculitis is a common cause. T cells infiltrate the kidney in cGN, but their precise role in autoimmunity is not known. Combined single-cell RNA sequencing and single-cell T-cell receptor sequencing were conducted on CD3 + T cells isolated from renal biopsies and blood of patients with ANCA-associated cGN and from kidneys of mice with experimental cGN. Functional and histopathological analyses were performed with Cd8a-/- and GzmB-/- mice. Single-cell analyses identified activated, clonally expanded CD8 + and CD4 + T cells with a cytotoxic gene expression profile in the kidneys of patients with ANCA-associated cGN. Clonally expanded CD8 + T cells expressed the cytotoxic molecule, granzyme B (GzmB), in the mouse model of cGN. Deficiency of CD8 + T cells or GzmB ameliorated the course of cGN. CD8 + T cells promoted macrophage infiltration and GzmB activated procaspase-3 in renal tissue cells, thereby increasing kidney injury. Clonally expanded cytotoxic T cells have a pathogenic function in immune-mediated kidney disease.