Kidney VISTA prevents IFNγ-IL-9 axis-mediated tubulointerstitial fibrosis after acute glomerular injury

Severe glomerular injury ultimately leads to tubulointerstitial fibrosis which determines patient outcome, but the immunological molecules connecting these two processes remain unresolved. The present study addressed whether V-domain Ig suppressor of T cell activation (VISTA), constitutively expressed in kidney macrophages, plays a protective role in tubulointerstitial fibrotic transformation after acute antibody-mediated glomerulonephritis. After acute glomerular injury using nephrotoxic serum, tubules in the VISTA-deficient (Vsir-/-) kidney suffered more damage than in wild type kidneys. When interstitial immune cells were examined, the contact frequency of macrophages with infiltrated T cells increased, and the immunometabolic features of T cells changed to high oxidative phosphorylation and fatty acid metabolism and overproduction of interferon-γ. The Vsir-/- parenchymal tissue cells responded to this altered milieu of interstitial immune cells as more interleukin-9 was produced, which augmented tubulointerstitial fibrosis. Blocking antibodies against interferon-γ and interleukin-9 protected the above pathological process in VISTA-depleted conditions. In human samples with acute glomerular injury (e.g., anti-neutrophil cytoplasmic autoantibody vasculitis), high VISTA expression in tubulointerstitial immune cells was associated with low tubulointerstitial fibrosis and good prognosis. Therefore, VISTA is a sentinel protein expressed in kidney macrophages that prevents tubulointerstitial fibrosis via the interferon-γ-interleukin-9 axis after acute antibody-mediated glomerular injury.