Transcriptional and Clonal Characterization of Cytotoxic T cells in Crescentic Glomerulonephritis.

BACKGROUND: Crescentic glomerulonephritis (cGN) is an aggressive form of immune-mediated kidney disease that is an important cause of end-stage renal failure. Anti-neutrophil cytoplasmic autoantibody (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 done 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.