Neutralizing the IL-7Rα limits injury in experimental ANCA-associated glomerulonephritis.

Abstract

Background and hypothesis: Increased T-cell interkeukin (IL)-7Rα signalling is associated with a poorer prognosis in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis. These studies examined the functional role of IL-7Rα (CD127) in experimental glomerulonephritis mediated by anti-myeloperoxidase (MPO) T-cell autoimmunity. We hypothesized that T cells would express IL-7Rα in the kidney and that blocking the function of IL-7Rα, without cellular depletion, would be protective.

Methods: Mice were immunized with mouse MPO, then low-dose sheep anti-mouse basement membrane globulin was administered to trigger glomerulonephritis. Flow cytometry and RNA-sequencing characterized intrarenal CD127+-expressing CD4+ and CD8+ T cells in mice with anti-MPO glomerulonephritis. To assess the functional role of IL-7Rα, mice with established anti-MPO autoimmunity were treated with anti-IL-7Rα antibodies.

Results: Control ovalbumin-immunized mice given anti-basement membrane globulin developed minimal injury, while MPO-immunized mice given anti-basement membrane globulin developed albuminuria with glomerular and tubulointerstitial injury. Numbers of intrarenal IL-7Rα+ (CD127+) CD4+ and CD8+ T cells were increased in mice with anti-MPO glomerulonephritis. There were 3738 and 2726 genes differentially expressed between intrarenal CD127-PD-1+ and CD127+PD-1- CD8+ and CD4+ T cells, respectively, with substantially overlapping differentially expressed genes between CD8+ and CD4+ T cells. Both CD127-PD-1+ CD8+ and CD4+ T cells were enriched for previously described T-cell exhaustion signatures associated with prognosis in autoimmune disease. As effector memory T cells drive inflammation, we blocked the IL-7Rα after inducing anti-MPO autoimmunity. Anti-IL-7Rα antibodies limited histological injury, and reduced albuminuria numbers of glomerular and interstitial leucocytes, with reduced intrarenal chemokine and pro-inflammatory cytokine expression.

Conclusions: Intrarenal effector memory and exhausted CD4+ and CD8+ T cells are present in experimental anti-MPO glomerulonephritis. Neutralizing effector T cells via the IL-7Rα after the induction of autoimmunity limits intrarenal inflammation and disease. IL-7Rα may be a therapeutic target in ANCA-associated vasculitis.