Transcriptional and Clonal Characterization of Cytotoxic T Cells in Crescentic Glomerulonephritis

Background 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. Methods 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. Results 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. Conclusions Clonally expanded cytotoxic T cells have a pathogenic function in immune-mediated kidney disease.

Automated summary

English Summary: Crescentic GN is a leading cause of end stage renal failure, and this study identified activated, clonally expanded cytotoxic T cells in the kidneys of patients with ANCA-associated cGN. The deficiency of these T cells ameliorated the disease progression, suggesting their pathogenic role in immune-mediated kidney disease.