Kidney dendritic cells: fundamental biology and functional roles in health and disease

Abstract

Dendritic cells (DCs) are chief inducers of adaptive immunity and regulate local inflammatory responses across the body. Together with macrophages, the other main type of mononuclear phagocyte, DCs constitute the most abundant component of the intrarenal immune system. This network of functionally specialized immune cells constantly surveys its microenvironment for signs of injury or infection, which trigger the initiation of an immune response. In the healthy kidney, DCs coordinate effective immune responses, for example, by recruiting neutrophils for bacterial clearance in pyelonephritis. The pro-inflammatory actions of DCs can, however, also contribute to tissue damage in various types of acute kidney injury and chronic glomerulonephritis, as DCs recruit and activate effector T cells, which release toxic mediators and maintain tubulointerstitial immune infiltrates. These actions are counterbalanced by DC subsets that promote the activation and maintenance of regulatory T cells to support resolution of the immune response and allow kidney repair. Several studies have investigated the multiple roles for DCs in kidney homeostasis and disease, but it has become clear that current tools and subset markers are not sufficient to accurately distinguish DCs from macrophages. Multidimensional transcriptomic analysis studies promise to improve mononuclear phagocyte classification and provide a clearer view of DC ontogeny and subsets.

Key points

  • Dendritic cells and macrophages constitute the most abundant component of the intrarenal immune system, but current tools and subset markers do not discriminate them clearly.

  • Modern sequencing methods, imaging mass cytometry and bioinformatic analysis allow superior classification and investigation of dendritic cells; these techniques have revealed that more subsets and functional states exist than previously thought.

  • Dendritic cells are sentinels that constantly survey the kidney microenvironment for injury or infection; they recruit and regulate immune effector cells such as macrophages, T cells and neutrophils to protect the host.

  • In acute kidney injury, kidney DCs are initially anti-inflammatory and limit immune-induced damage.

  • When kidney inflammation becomes chronic, dendritic cells undergo functional changes and might promote progression of kidney disease.

  • Dendritic cells might be modified therapeutically by targeting the chemokines that regulate their migration or the transcription factors that control their development and/or differentiation.

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Fig. 1: Mononuclear phagocyte ontogeny and subsets.
Fig. 2: Migration of kidney DCs.
Fig. 3: Location of dendritic cells in the kidney.
Fig. 4: DCs regulate kidney disease through crosstalk with immune effector cells.
Fig. 5: Roles of DC function throughout the course of crescentic glomerulonephritis.

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Acknowledgements

The authors apologize to all colleagues whose work could not be cited owing to space restrictions. We thank C. Meyer Schwesinger for providing images of kidney DCs and C. Krebs for help with Fig. 5. C.K. was supported by the Deutsche Forschungsgemeinschaft (Gottfried-Wilhelm Leibniz Award, SFB1192 project A8, SFBTR57 project 10, Germany’s Excellence Strategy EXC 2151-390873048), and the European Union Horizon 2020 research and innovation programme (grant agreement 668036 ʻRELENTʼ). F.G. was supported by the core funding of the Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR). U.P. was supported by the Deutsche Forschungsgemeinschaft SFB1192 project A1.

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Glossary

Tolerance

A process whereby potentially harmful autoimmune responses driven by self-reactive immune cells are limited; for example, DCs that present autoantigens can induce apoptosis of self-reactive T cells.

Cross-presentation

The uptake, processing and presentation of extracellular antigens on major histocompatibility complex class I to CD8 T cells.

Fibroblastic reticular cells

Cells that produce a scaffold of dense fibres within lymphoid tissue and regulate lymphocytes through the production of cytokines.

Bone marrow chimaeras

Mice that have been irradiated and then transplanted with bone marrow cells from a different animal.

Dendrites

Cell surface protrusions reminiscent of tree (dendron) branches that gave dendritic cells their name; these protrusions increase the cell surface area and permit interaction with many T cells.

Bulk draining

Cell-independent transport of antigens from an organ to its draining lymph node by lymph flow.

Transcytosis

A type of transcellular transport whereby macromolecules are endocytosed, transported in vesicles across the interior of a cell and exocytosed.

M2-associated genes

Genes expressed by anti-inflammatory, regenerative macrophages.

Tolerogenic DCs

Dendritic cells that induce T cell tolerance.

Cellular hypersensitivity

Exaggerated inflammatory responses mediated by immune cells that result in tissue injury.

Neoantigens

Novel antigens not previously present in an organism; such antigens can result, for example, from genetic mutations in malignant cells.

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Kurts, C., Ginhoux, F. & Panzer, U. Kidney dendritic cells: fundamental biology and functional roles in health and disease. Nat Rev Nephrol 16, 391–407 (2020). https://doi.org/10.1038/s41581-020-0272-y

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