Neutralizing the IL-7Ra limits injury in ANCA-associated glomerulonephritis
Increased T cell IL-7Ra (CD127) signaling is associated with poor prognosis in ANCA-associated vasculitis patients, whereas genes linked to T cell exhaustion such as PD-1 correlate with fewer relapses and better patient outcomes. This study characterised intrarenal CD127 and PD-1 expressing CD4+ and CD8+ T cells in mice with anti-MPO glomerulonephritis by RNA sequencing and examined the functional role of IL-7Ra in experimental glomerulonephritis mediated by anti-MPO T cell autoimmunity. There were 3,738 and 2,726 genes differentially expressed between intrarenal CD127-PD-1+ and CD127+PD-1- CD8+ and CD4+ T cells, respectively, with a substantial overlap of 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 that predict prognosis in autoimmune disease. As effector memory T cells drive inflammation, we blocked CD127 after the induction of anti-MPO autoimmunity. Compared with control IgG, anti-IL-7Ra antibodies limited histological injury, reduced albuminuria and reduced numbers of glomerular and interstitial leukocytes, with reduced intrarenal chemokine and pro-inflammatory cytokine expression. Intrarenal effector memory and exhausted CD4+ and CD8+ T cells are present in experimental anti-MPO glomerulonephritis. Neutralising effector memory T cells via the IL-7Ra after the induction of autoimmunity limits intrarenal inflammation and disease. IL-7Ra may be a therapeutic target in ANCA-associated vasculitis. Overall design: Mice were immunised with recombinant mouse MPO and then low-dose sheep anti-mouse basement membrane (BM) globulin was administered to trigger glomerulonephritis. Twenty-one days later, kidneys were isolated and the following cells were flow sorted: CD4+CD127+PD-1-, CD4+CD127-PD-1+, CD8+CD127+PD-1- and CD8+CD127-PD-1+. Pooled cells from three mice were used for the sorting and there were three experiments per group except for sample CD4+CD127-PD-1+ because it failed quality control. We then performed gene expression profiling to investigate the the differentially expressed genes between the four populations.