Kidney dendritic cell activation is required for progression of renal disease in a mouse model of glomerular injury
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
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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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 5

DCs are essential for periglomerular infiltration.

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DCs are essential for periglomerular infiltration. (A) 4 ng/g body weigh...
(A) 4 ng/g body weight DT was injected into WT, NOH, or NOH × CD11c-DTR mice that had received 5 × 106 OT-I cells and 5 × 106 activated OT-II cells 5 days before. After an additional 40 hours, kidney single-cell suspensions were examined for surviving DCs by flow cytometry for CD11c+ and eGFP expression within the transgene. Dot plots show representative results, and a quantitative analysis is given in the same panel to the right. Numbers in quadrants of dot plots indicate the proportion of cells. (B–G) 5 × 106 OT-I cells and 5 × 106 activated OT-II cells were injected into NOH × CD11c-DTR (B and C) or NOH mice (D and E). After 5 days, DT was injected (B and C). Kidney sections were scored after 40 hours for frequency (F) and severity (G) of infiltrates. Representative H&E stainings are shown in B–E. Scale bars: 400 μm. Semiquantitative analyses show 2 further controls: non-Tg mice injected with DT and NOH mice not injected with DT. Symbols indicate sections from individual mice and the bars their mean. Results are representative of 2 experiments. *P < 0.05; **P < 0.01; ***P < 0.001. Data are presented as mean ± SD.