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J Clin Invest. 2018 Aug 1;128(8):3413-3424. doi: 10.1172/JCI97879. Epub 2018 Jul 9.

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

Author information

1
Division of Nephrology, Zhongshan Hospital, affiliated with Xiamen University, Xiamen, Fujian Province, China.
2
Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
3
Department of Pathology, Columbia University Medical Center, New York, New York, USA.
4
Renal Section, James J. Peters VA Medical Center, Bronx, New York, USA.
5
Institute of Precision Immunology, Icahn School of Medicine at Mount Sinai, New York New York, USA.

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.

KEYWORDS:

Chronic kidney disease; Immunology; Nephrology; T cells

PMID:
29985168
PMCID:
PMC6063505
DOI:
10.1172/JCI97879
[Indexed for MEDLINE]
Free PMC Article

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