Kidney dendritic cell activation is required for progression of renal disease in a mouse model of glomerular injury
Felix Heymann, … , Hermann-Josef Gröne, Christian Kurts
Felix Heymann, … , Hermann-Josef Gröne, Christian Kurts
Published April 20, 2009
Citation Information: J Clin Invest. 2009;119(5):1286-1297. https://doi.org/10.1172/JCI38399.
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Research Article

Kidney dendritic cell activation is required for progression of renal disease in a mouse model of glomerular injury

Abstract

The progression of kidney disease to renal failure correlates with infiltration of mononuclear immune cells into the tubulointerstitium. These infiltrates contain macrophages, DCs, and T cells, but the role of each cell type in disease progression is unclear. To investigate the underlying immune mechanisms, we generated transgenic mice that selectively expressed the model antigens ovalbumin and hen egg lysozyme in glomerular podocytes (NOH mice). Coinjection of ovalbumin-specific transgenic CD8+ CTLs and CD4+ Th cells into NOH mice resulted in periglomerular mononuclear infiltrates and inflammation of parietal epithelial cells, similar to lesions frequently observed in human chronic glomerulonephritis. Repetitive T cell injections aggravated infiltration and caused progression to structural and functional kidney damage after 4 weeks. Mechanistic analysis revealed that DCs in renal lymph nodes constitutively cross-presented ovalbumin and activated CTLs. These CTLs released further ovalbumin for CTL activation in the lymph nodes and for simultaneous presentation to Th cells by distinct DC subsets residing in the kidney tubulointerstitium. Crosstalk between tubulointerstitial DCs and Th cells resulted in intrarenal cytokine and chemokine production and in recruitment of more CTLs, monocyte-derived DCs, and macrophages. The importance of DCs was established by the fact that DC depletion rapidly resolved established kidney immunopathology. These findings demonstrate that glomerular antigen–specific CTLs and Th cells can jointly induce renal immunopathology and identify kidney DCs as a mechanistic link between glomerular injury and the progression of kidney disease.

Authors

Felix Heymann, Catherine Meyer-Schwesinger, Emma E. Hamilton-Williams, Linda Hammerich, Ulf Panzer, Sylvia Kaden, Susan E. Quaggin, Jürgen Floege, Hermann-Josef Gröne, Christian Kurts

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Figure 1

Generation and characterization of mice expressing model autoantigens in glomeruli.

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Generation and characterization of mice expressing model autoantigens in...
(A) Plasmid used to generate NOH mice. (B) Kidney sections of a NOH (left) and non-Tg control (right) mouse stained for OVA expression. Red, OVA; blue, nuclei. Original magnification, ×1,000. (C) Division indices of CFSE-labeled OT-I cells in various LNs and the spleen of NOH and non-Tg mice on day 3 after adoptive transfer. (D) CFSE-labeled OT-I cells were injected into NOH × CD11c-DTR, NOH, or non-Tg mice, and DCs were depleted by injection of DT on the same day. Bars indicate division indices of OT-I cells in the renal LN on day 3. nOT-I, naive OT-I. (E) CD69 expression of CFSE-labeled OT-II cells in the renal LN of NOH and non-Tg mice on day 3 after transfer. In vitro–activated OT-II cells were used as positive staining control. Representative flow cytometry data for C and D appear in Supplemental Figure 2. Results are representative of 3 experiments in groups of 3 mice. Data are presented as mean ± SD. aOT-II, activated OT-II cells.