SFB 1192
Project A2
Investigating the links between pathogenicity and antigen specificity of cytotoxic T lymphocytes in crescentic glomerulonephritis
Immune-mediated glomerular diseases such as crescentic glomerulonephritis (cGN), often caused by anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis, are driven by inappropriately activated infiltrating T cells, which induce local inflammation and decline in kidney function. However, the antigen specificity and clonality of these kidney-infiltrating T cells, as well as their pathogenic effector mechanisms leading to injury in cGN are largely obscure. In project A2, we demonstrated a pathogenic function of cytotoxic CD8+ T cells in experimental cGN and showed that granzyme B is a mediator and potential therapeutic target in immune-mediated kidney disease. When directly analyzing T cells in the kidneys of patients with ANCA-associated cGN (ANCA-GN) via combined single-cell RNA sequencing (scRNA-seq) and single-cell T cell receptor sequencing (scTCR-seq), we identified clonally expanded cytotoxic CD8+ T cells, but also cytotoxic CD4+ and γδ T cells. Now, we aim at clarifying the contribution of these different types of cytotoxic T lymphocytes (CTLs) to disease pathology of cGN. We will explore the location, interaction partners and cellular targets of cytotoxic CD4+, CD8+ and γδ T cells. Furthermore, we will investigate the specific (auto-)antigens that are recognized by these CTLs. To achieve this, we have the following specific aims:
1. To define how chronic inflammation in human and experimental cGN drives the activation and accumulation of cytotoxic CD4+, CD8+ and γδ T cells in the kidneys and vice versa how these CTLs contribute to renal injury. 2) To map the precise location of cytotoxic CD4+, CD8+ and γδ T cells and their potential target cells in ANCA-GN on the clonal level. 3) To screen and predict the (auto)-antigens recognized by the TCRs of CD4+, CD8+ and γδ CTLs in cGN.
Our studies addressing the mechanisms and specific auto-antigens that lead to CTL activation in inflamed kidneys are essential to design the next generation of individualized therapies targeting pathogenic CTLs in cGN.
Publication
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Transcriptional and Clonal Characterization of Cytotoxic T cells in Crescentic Glomerulonephritis.
Anne Mueller, Yu Zhao, Hakan Cicek, Hans-Joachim Paust, Amirrtavarshni Sivayoganathan, Alexandra Linke, Claudia Wegscheid, Thorsten Wiech, Tobias B Huber, Catherine Meyer-Schwesinger, Stefan Bonn, Immo Prinz, Ulf Panzer, Gisa Tiegs, Christian F Krebs, Katrin NeumannAm Soc Nephrol. 2023 Mar
Project-Team
Project Leader
PD Dr. rer. nat. Katrin Neumann
Prof. Dr. rer. nat. Immo Prinz
Prof. Dr. rer. nat. Stefan Bonn