CD103+ Kidney Dendritic Cells Protect against Crescentic GN by Maintaining IL-10-Producing Regulatory T Cells

Abstract

Kidney dendritic cells (DCs) regulate nephritogenic T cell responses. Most kidney DCs belong to the CD11b⁺ subset and promote crescentic GN (cGN). The function of the CD103⁺ subset, which represents <5% of kidney DCs, is poorly understood. We studied the role of CD103⁺ DCs in cGN using several lines of genetically modified mice that allowed us to reduce the number of these cells. In all lines, we detected a reduction of FoxP3⁺ intrarenal regulatory T cells (T_regs), which protect against cGN. Mice lacking the transcription factor Batf3 had a more profound reduction of CD103⁺ DCs and T_regs than did the other lines used, and showed the most profound aggravation of cGN. The conditional reduction of CD103⁺ DC numbers by 50% in Langerin-DTR mice halved T_reg numbers, which did not suffice to significantly aggravate cGN. Mice lacking the cytokine Flt3L had fewer CD103⁺ DCs and T_regs than Langerin-DTR mice but exhibited milder cGN than did Batf3^-/- mice presumably because proinflammatory CD11b⁺ DCs were somewhat depleted as well. Conversely, Flt3L supplementation increased the number of CD103⁺ DCs and T_regs, but also of proinflammatory CD11b⁺ DCs. On antibody-mediated removal of CD11b⁺ DCs, Flt3L supplementation ameliorated cGN. Mechanistically, CD103⁺ DCs caused cocultured T cells to differentiate into T_regs and produced the chemokine CCL20, which is known to attract T_regs into the kidney. Our findings show that CD103⁺ DCs foster intrarenal FoxP3⁺ T_reg accumulation, thereby antagonizing proinflammatory CD11b⁺ DCs. Thus, increasing CD103⁺ DC numbers or functionality might be advantageous in cGN.

Keywords: dendritic cells; glomerulonephritis; immunology; lymphocytes; regulatory T cells.