Bowman’s capsule provides a protective niche for podocytes from cytotoxic CD8+ T cells
Anqun Chen, … , Detlef Schlondorff, Judith Agudo
Anqun Chen, … , Detlef Schlondorff, Judith Agudo
Published July 9, 2018
Citation Information: J Clin Invest. 2018;128(8):3413-3424. https://doi.org/10.1172/JCI97879.
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Concise Communication Immunology Nephrology

Bowman’s capsule provides a protective niche for podocytes from cytotoxic CD8+ T cells

Abstract

T cells play a key role in immune-mediated glomerulonephritis, but how cytotoxic T cells interact with podocytes remains unclear. To address this, we injected EGFP-specific CD8+ T cells from just EGFP death inducing (Jedi) mice into transgenic mice with podocyte-specific expression of EGFP. In healthy mice, Jedi T cells could not access EGFP+ podocytes. Conversely, when we induced nephrotoxic serum nephritis (NTSN) and injected Jedi T cells, EGFP+ podocyte transgenic mice showed enhanced proteinuria and higher blood urea levels. Morphometric analysis showed greater loss of EGFP+ podocytes, which was associated with severe crescentic and necrotizing glomerulonephritis. Notably, only glomeruli with disrupted Bowman’s capsule displayed massive CD8+ T cell infiltrates that were in direct contact with EGFP+ podocytes, causing their apoptosis. Thus, under control conditions with intact Bowman’s capsule, podocytes are not accessible to CD8+ T cells. However, breaches in Bowman’s capsule, as also noted in human crescentic glomerulonephritis, allow access of CD8+ T cells to the glomerular tuft and podocytes, resulting in their destruction. Through these mechanisms, a potentially reversible glomerulonephritis undergoes an augmentation process to a rapidly progressive glomerulonephritis, leading to end-stage kidney disease. Translating these mechanistic insights to human crescentic nephritis should direct future therapeutic interventions at blocking CD8+ T cells, especially in progressive stages of rapidly progressive glomerulonephritis.

Authors

Anqun Chen, Kyung Lee, Vivette D. D’Agati, Chengguo Wei, Jia Fu, Tian-Jun Guan, John Cijiang He, Detlef Schlondorff, Judith Agudo

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Figure 1

Effects of Jedi T cell injections on normal pod-EGFP mice.

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Effects of Jedi T cell injections on normal pod-EGFP mice. (A) Time cour...
(A) Time course for the experimental protocol. Four days after intraperitoneal injection of PBS (0.1 ml), pod-EGFP mice were coinjected with LV.EGFP and either control T cells (n = 4) or Jedi T cells (n = 4). Mice with PBS injection only served as controls (n = 4). (B) Urinary albumin-to-creatinine ratios (UACR, μg/μg) tested for all time points were within the normal range (<0.15 μg/μg) for both PBS plus control T cell– and PBS plus Jedi T cell–injected mice. (C) Representative H&E-stained images of pod-EGFP kidneys. Original magnification, ×200 (upper panels); ×600 (lower panels). (D) Representative images of EGFP fluorescence (top row) and merged images of EGFP, DAPI, and differential interference contrast (DIC) to identify glomeruli and tubules (bottom row). Scale bar: 50 μm. (E and F) Quantification of the EGFP+ area in pod-EGFP mice, as EGFP+ area per glomerulus (glom) (E) and size distribution curves for EGFP+ area per glomerulus (F) (n = 4 mice, 381 glomeruli analyzed for PBS-only group; n = 4 mice, 442 glomeruli analyzed for PBS plus control T cell group; n = 4 mice, 420 glomeruli analyzed for PBS plus Jedi T cell groups).