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

• Published in: The Journal of clinical investigation Vol. 128; no. 8; pp. 3413 - 3424
• Main Authors: Chen, Anqun, Lee, Kyung, D'Agati, Vivette D, Wei, Chengguo, Fu, Jia, Guan, Tian-Jun, He, John Cijiang, Schlondorff, Detlef, Agudo, Judith
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01.08.2018
• Subjects: Nephrology; Chronic kidney disease; Immunology; T cells
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI97879

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.