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Dendritic cells in intestinal immune regulation

Key Points

  • An important feature of the intestinal immune system is its ability to protect against infection while avoiding the development of destructive inflammatory responses to the normal microbiota and dietary antigens.

  • Populations of intestinal dendritic cells (DCs) display unique functional properties. They have been implicated both in the maintenance of tolerance towards harmless antigens, and in the generation of protective immune responses against pathogens.

  • Recent data suggests that intestinal DCs can promote differentiation of forkhead box P3 (FOXP3)+ regulatory T cells from naive precursors. Transforming growth factor-β and retinoic acid have an important role in this process.

  • Conditioning of DCs in their local tissue environment may have an important role in shaping their function.

  • A breakdown in intestinal homeostasis can result in chronic inflammatory diseases of the gut including inflammatory bowel disease. Inappropriate or aberrant DC function may have a role in the pathogenesis of inflammatory bowel disease.

Abstract

A breakdown in intestinal homeostasis can result in chronic inflammatory diseases of the gut including inflammatory bowel disease, coeliac disease and allergy. Dendritic cells, through their ability to orchestrate protective immunity and immune tolerance in the host, have a key role in shaping the intestinal immune response. The mechanisms through which dendritic cells can respond to environmental cues in the intestine and select appropriate immune responses have until recently been poorly understood. Here, we review recent work that is beginning to identify factors responsible for intestinal conditioning of dendritic-cell function and the subsequent decision between tolerance and immunity in the intestine.

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Figure 1: Role of vitamin A metabolites in intestinal DC function.
Figure 2: Conditioning of DCs in the intestine.
Figure 3: Response of intestinal DCs to infection.

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Acknowledgements

The authors are supported by the Wellcome trust (F.P.), the European Union (Euro-Thymaide FP6 Integrated Project; LSHB-CT-2003-503410), and the Medical Research Council (J.C.).

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Correspondence to Fiona Powrie.

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Glossary

Inflammatory bowel disease

(IBD). A group of conditions, of unknown aetiology, in which the intestinal mucosa is chronically inflammed. Includes Crohn's disease and ulcerative colitis.

Plasmacytoid DC

(pDCs). A subset of dendritic cells (DCs) the microscopic appearance of which resembles plasmablasts. In humans, these DCs can be derived from lineage-negative stem cells in peripheral blood and are the main producers of type I interferons (IFNs) in response to virus infections. Recent studies have identified subsets of type-I-IFN-producing DCs in mice, which are identified by expression of B220, Ly6C and other markers.

M cells

(Microfold cells). Specialized epithelial cells that deliver antigens by transepithelial vesicular transport from the gut lumen directly to intraepithelial lymphocytes and to subepithelial lymphoid tissues.

Regulatory T cell

(TReg cell). A type of CD4+ T cell that is characterized by its expression of forkhead box P3 (FOXP3) and high levels of CD25. TReg cells can downmodulate many types of immune responses. CD4+CD25+FOXP3+ TReg cells that develop in the thymus are exported to the periphery with their regulatory function already intact. However, FOXP3+ T cells with regulatory function can also be generated in the periphery from naive CD4+ T cells following, for example, the oral administration of antigen or targeting of peptide ligands to dendritic cells in vivo.

TH17 cells

(T helper 17 cells). A subset of CD4+ T helper cells that produce interleukin-17 (IL-17) and that are thought to be important in inflammatory and autoimmune diseases. Their generation involves IL-6, TGFβ (transforming growth factor-β), IL-23 and IL-21, as well as the transcription factors RORγt (retinoic-acid-receptor-related orphan receptor-γt) and STAT3 (signal transducer and activator of transcription 3).

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Coombes, J., Powrie, F. Dendritic cells in intestinal immune regulation. Nat Rev Immunol 8, 435–446 (2008). https://doi.org/10.1038/nri2335

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