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  • Review Article
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Anatomical basis of tolerance and immunity to intestinal antigens

Nature Reviews Immunology volume 3, pages 331–341 (2003)Cite this article

Key Points

  • The intestinal immune system is an anatomically and functionally distinct compartment, in which a careful distinction must be made between harmful antigens, such as invasive pathogens, and harmless antigens, such as dietary proteins or commensal bacteria.

  • The default response to harmless antigens is the induction of tolerance. A breakdown in this physiological process can lead to disease.

  • Immune responses and tolerance in the gut are initiated in organized lymphoid organs, such as the Peyer's patches and mesenteric lymph nodes (MLNs). The mucosa contains effector or regulatory cells that migrate there selectively, from the MLNs, in the lymph and bloodstream under the control of α4β7 integrins and the chemokine receptor CCR9.

  • Pathogens might enter the intestinal immune system through M cells in the follicle-associated epithelium of the Peyer's patches, whereas soluble antigens might gain access predominantly through the normal epithelium that covers the villus mucosa.

  • Peyer's patches, lamina propria and MLNs contain unusual populations of dendritic cells (DCs), some of which are characterized by the production of interleukin-10 (IL-10) and which polarize T cells to an IL-4-, IL-10- and transforming growth factor-β (TGF-β)-producing 'regulatory' phenotype.

  • Genetically determined factors, together with luminal bacteria, might act on epithelial and stromal components of the intestinal mucosa to produce a local microenvironment that is dominated by the constitutive production of prostaglandin E2 (PGE2), TGF-β and IL-10. Under physiological conditions, this favours the differentiation of regulatory DCs and T cells, which leads to systemic tolerance and/or immunoglobulin-A production.

Abstract

The intestinal immune system has to discriminate between harmful and beneficial antigens. Although strong protective immunity is essential to prevent invasion by pathogens, equivalent responses against dietary proteins or commensal bacteria can lead to chronic disease. These responses are normally prevented by a complex interplay of regulatory mechanisms. This article reviews the unique aspects of the local microenvironment of the intestinal immune system and discuss how these promote the development of regulatory responses that ensure the maintenance of homeostasis in the gut.

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Figure 1: Schematic representation of the lymphoid elements of the intestinal immune system.
Figure 2: Histological appearance of Peyer's patches and intestinal mucosa.
Figure 3: Antigen uptake and recognition by CD4+ T cells in the intestine.
Figure 4: Model of the role of the intestinal microenvironment in polarizing immune functions.

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Acknowledgements

I would like to thank L. Cousins for critical review of the manuscript.

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  1. Department of Immunology and Bacteriology, Western Infirmary, Glasgow, G11 6NT, UK

    Allan McI. Mowat

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  1. Allan McI. Mowat
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DATABASES

LocusLink

α4β7 integrin

CCL25

CCR4

CCR9

CD2

COX2

IFN-γ

IL-1

IL-4

IL-7

IL-10

IL-12

LIGHT

L-selectin

LTα1β2

LTβR

MADCAM1

MIP3α

RANK

RANK-ligand

TGF-β

VCAM1

VLA4

OMIM

Coeliac disease

Crohn's disease

Glossary

COELIAC DISEASE

A chronic inflammatory condition of the upper small intestine in humans that is caused by immunological hypersensitivity to the α-gliadin component of wheat gluten. It is often found in infants after the introduction of solid foods. It causes severe villus atrophy, which can lead to malabsorption and malnutrition if gluten-containing foods are not removed from the diet.

CROHN'S DISEASE

A form of chronic inflammatory bowel disease that can affect the entire gastrointestinal tract, but is commonest in the colon and terminal ileum. It is characterized by transmural inflammation, strictures and granuloma formation, and is believed to result from an abnormal T-cell-mediated immune response to commensal bacteria.

BRUSH BORDER

The surface layer of the normal small intestine that is comprised of small microvilli coated in a rich glycocalyx of mucus and other glycoproteins. The microvilli contain many of the digestive enzymes and transporter systems that are involved in the metabolism and uptake of dietary materials. The brush border provides a large surface area for absorption.

INFLAMMATORY BOWEL DISEASE

A chronic condition of the intestine that is characterized by severe inflammation and mucosal destruction. The commonest forms in humans are ulcerative colitis and Crohn's disease. Animal models indicate that they result from the dysregulation of the local immune response to normally harmless commensal bacteria.

EXOSOMES

Small lipid-bilayer vesicles that are released from dendritic cells and other cells. They are comprised of either cell membranes or the membranes of intracellular vesicles. They might contain antigen–MHC complexes and interact with antigen-specific lymphocytes directly, or they might be taken up by further antigen-presenting cells.

PLASMACYTOID DENDRITIC CELLS

A subset of dendritic cells (DCs) with a microscopic appearance similar to plasmablasts. In humans, these DCs are the main producers of type I interferon (IFN) in response to virus infections. Recent studies have identified a similar subset of type I IFN-producing DCs in mice, which are characterized by expression of B220 and Ly6C/G, and which might be tolergenic in nature.

DANGER SIGNALS

Cell-wall components and other products of pathogens that alert the innate immune system to the presence of potentially harmful invaders, usually by interacting with Toll-like receptors and other pattern-recognition receptors expressed by tissue cells and dendritic cells, for example.

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Mowat, A. Anatomical basis of tolerance and immunity to intestinal antigens. Nat Rev Immunol 3, 331–341 (2003). https://doi.org/10.1038/nri1057

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  • DOI: https://doi.org/10.1038/nri1057

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