Targeting tissue-resident memory T cell in autoimmune kidney disease

• Applicant: Professor Dr. Christian Krebs
• Subject Area: Nephrology ; Immunology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 497529203

A chronic remitting clinical course is a common feature of autoimmune diseases, but the underlying cellular and molecular mechanisms are incompletely understood so far. It is reasonable to assume that long-lived immune cells are involved in local inflammation reactions and the resulting organ damage. Tissue-resident memory T cells (Trm) are a recently found memory T cell subset that is defined by its exclusion from circulation. Trm cells can act as local sentinels for pathogens but could also contribute to autoimmune reactions. We have identified Trm cells with expression profiles of Th17 cells (termed Trm17) in the kidney of patients with glomerulonephritis and in the lung of COVID-19 patients. Our experimental data show that renal Trm17 cells can be induced by pathogens such as S. aureus and E. coli. Importantly, renal Trm17 cells can be reactivated in inflammatory settings to aggravate organ damage in immune-mediated diseases. Here we plan to perform high dimensional profiling of Trm cell subsets from kidney biopsies of patients with different forms of immune-mediated kidney disease and from control kidneys. In addition, we will analyze renal Trm17 cells from experimental animal models. Specifically, we will combine gene expression analysis, cell surface protein measurement, TCR-sequencing and chromatin accessibility of T cells from the kidney at the single cell level. These analyses will enable us to identify and validate therapeutic targets on Trm cells. Based on these new results and already available data, we plan to design and test tissue-penetrating nanobodies including heavy-chain only antibodies as well as bi- and tri-specific killer cell engagers (BiKEs and TriKEs) for a specific depletion of pathogenic Trm cells. The intention of this study is to provide treatment strategies for chronic remitting immune-mediated diseases by targeting Trm cells within the renal tissue. Importantly, the nanobodies generated in this project for Trm cell depletion can readily be tested in first-in-human studies.

• DFG Programme: Research Grants