Kidney VISTA prevents IFN-γ/IL-9 axis–mediated tubulointerstitial fibrosis after acute glomerular injury
Min-Gang Kim, … , Dong-Sup Lee, Seung Seok Han
Min-Gang Kim, … , Dong-Sup Lee, Seung Seok Han
Published November 9, 2021
Citation Information: J Clin Invest. 2022;132(1):e151189. https://doi.org/10.1172/JCI151189.
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Research Article Nephrology

Kidney VISTA prevents IFN-γ/IL-9 axis–mediated tubulointerstitial fibrosis after acute glomerular injury

Abstract

Severe glomerular injury ultimately leads to tubulointerstitial fibrosis that determines patient outcome, but the immunological molecules connecting these processes remain undetermined. 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 those in WT 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 showing high oxidative phosphorylation and fatty acid metabolism and overproduction of IFN-γ. The Vsir–/– parenchymal tissue cells responded to this altered milieu of interstitial immune cells as more IL-9 was produced, which augmented tubulointerstitial fibrosis. Blocking antibodies against IFN-γ and IL-9 protected the above pathological process in VISTA-depleted conditions. In human samples with acute glomerular injury (e.g., antineutrophil 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 IFN-γ/IL-9 axis after acute antibody-mediated glomerular injury.

Authors

Min-Gang Kim, Donghwan Yun, Chae Lin Kang, Minki Hong, Juhyeon Hwang, Kyung Chul Moon, Chang Wook Jeong, Cheol Kwak, Dong Ki Kim, Kook-Hwan Oh, Kwon Wook Joo, Yon Su Kim, Dong-Sup Lee, Seung Seok Han

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Figure 3

Immunometabolic changes in T cells.

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Immunometabolic changes in T cells. (A) UMAP plots of 7396 sorted immune...
(A) UMAP plots of 7396 sorted immune cells. (B) Dot plot to identify clusters of immune cells. pDC, plasmacytoid dendritic cell; NKT, NK T cell; ILC2, type 2 innate lymphoid cell. (C) Proportions of all cell types in WT and Vsir–/– kidneys (upper). Proportions of EM-like T cells within each T cell lineage (lower). (D) Heatmap of logarithmic fold changes of cytokine genes in T cells from Vsir–/– mice compared with WT mice. (E) Hallmark gene set enrichment analysis in order of normalized enrichment score (ES). (F) Correlation between metabolic features and Ifng level in EM-like T cells. Line and area represent nonlinear relationship and 95% CIs, respectively. Blue and red dots represent T cells obtained from the kidneys of WT and Vsir–/– mice, respectively. (G) Proportions of T cell subsets evaluated by flow cytometry (n = 7 per group). TN, naive T cells; TEM, effector memory T cells; TE, effector T cells; TCM, central memory T cells. (H) Proportions of cytokine-producing T cells evaluated by flow cytometry (n = 11 per group). (I) Proportions of IFN-γ+ cells in CD4+, CD8+, and other immune cells (n = 11 per group). P values were calculated using an unpaired Student’s t test for 2 groups or ANOVA with Tukey’s test for multiple comparison. *P < 0.05; **P < 0.01; ***P < 0.001. Data represent 2 or 3 independent experiments.