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

Abstract

<p class="first" id="d1936236e228">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. </p>