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  • Review Article
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Man the barrier! strategic defences in the intestinal mucosa

Nature Reviews Immunology volume 1, pages 59–67 (2001) Cite this article

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Key Points

  • Most antigens enter the body at mucosal surfaces. Unique adaptations support the barrier function of the intestinal epithelium.

  • The gut-associated lymphoid tissue (GALT) is divided into discrete inductive (Peyer's patch and mesenteric lymph node; MLN) and effector (lamina propria) sites that contain specialized populations of B (IgA) and T cells.

  • The accumulation of memory T-effector cells at epithelial surfaces 'man the barriers' for strategic mucosal defense.

  • Toll-like receptors (TLRs) recognize microbial structures that are common to both pathogens and commensals. Although commensals can gain access to the GALT, only pathogens elicit an adaptive immune response.

  • The intestinal epithelium has an important role in orchestrating immune responses in the GALT by generating both pro-inflammatory and anti-inflammatory signals.

  • The factors controlling responsiveness to pathogens and nonresponsiveness to innocuous antigens from food or commensals are delicately balanced. Mucosal dysregulation leads to chronic intestinal inflammation.

  • Food proteins typically induce systemic nonresponsiveness (oral tolerance). As in the periphery, dendritic cells (DCs) have a primary role in the presentation of antigen to naive T cells in the GALT.

  • Nonresponsiveness to food proteins is originally manifested as a reduction in the proliferative capacity of antigen-specific T cells in the draining MLN. This is likely to be due to the preferential binding of cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), to low levels of the co-stimulatory molecules CD80/CD86 in the absence of inflammatory signals.

  • High-level production of anti-inflammatory mediators, such as interleukin-10 and prostaglandin E2, in the GALT make it a headquarters for the generation of regulatory T cells.

Abstract

Immunologists typically study the immune responses induced in the spleen or peripheral lymph nodes after parenteral immunization with antigen and poorly defined experimental adjuvants. However, most antigens enter the body through mucosal surfaces. It is now clear that the microenvironment in these mucosal barriers has a marked influence on the immune response that ultimately ensues. Nowhere is the microenvironment more influential than in the gut-associated lymphoid tissue (GALT). The GALT must constantly distinguish harmless antigens that are present in food or on commensal bacteria from pathogenic assault by microbes. It is perhaps not surprising, then, that the GALT contains more lymphocytes than all of the secondary lymphoid organs combined.

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Figure 1: Antigens enter through mucosal surfaces.
Figure 2: Gut-associated lymphoid tissue.

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Acknowledgements

This work was supported by National Institutes of Health and by the Center for the Study of Inflammatory Bowel Disease at Massachusetts General Hospital and the Clinical Nutrition Research Center at Harvard. I thank the members of my laboratory for their contributions to both the work cited and the writing of this manuscript, particularly: H.N. Shi, E. Melendro, M. Bashir, D. Smith, P. Andersen and O. Iweala. Thanks are also extended to B. McCormick, B. Cherayil, A. Bhan and D. Podolsky for critical review of the manuscript.

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  1. Department of Pediatrics, Massachusetts General Hospital and Harvard Medical School, Building 114, 16th Street, Room 3600, Charlestown, 02129, Massachusetts, USA

    Cathryn Nagler-Anderson

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NOD2

pIgR

TGF-β

TLR

OMIM

Crohn's disease

Glossary

TIGHT JUNCTIONS

A ring of proteins that seals apical epithelium; includes the integral membrane proteins occludin and claudin, in association with cytoplasmic zonula occludins proteins.

DEFENSINS

Anti-microbial peptides secreted by Paneth cells in the villus crypt.

TREFOIL PEPTIDES

Three small proteins, secreted by goblet cells, which function in epithelial protection and repair5.

SECRETORY COMPONENT

Fragment of the polymeric immunoglobulin receptor receptor that is left attached to secretory IgA after its transport to the apical surface of epithelial cells.

TRANSFORMING GROWTH FACTOR-β

(TGF-β). A pleotropic anti-inflammatory cytokine produced by activated T cells and mononuclear phagocytes as well as other cell types. The effects of TGF-β are mainly anti-proliferative. It antagonizes the actions of pro-inflammatory cytokines by inhibiting both macrophage activation and T-cell proliferation and differentiation.

ARACHIDONIC ACID METABOLITES

A family of lipid mediators with diverse biological activities. The products of the lipooxygenase and cyclooxygenase (COX) pathways, leukotrienes and prostaglandins, respectively, are important mediators of the allergic inflammatory response. Prostaglandin E2 has immunomodulatory effects in the small intestinal lamina propria, where it is secreted at high levels due to the constitutive production of COX2.

CRYPTOPATCHES

Clusters of c-kit+IL-7R+Thy1+ T-cell progenitors found in the crypt lamina propria of both small and large intestinal villi.

VASCULAR ADDRESSINS

Mucin-like molecules, expressed on endothelial cells, to which leukocyte-adhesion molecules (homing receptors) bind. Vascular addressins have a central role in guiding the selective homing of lymphocytes to various body sites. In the mucosa, the mucosal addressin cell-adhesion molecule-1 (MadCAM-1) binds to both L-selectin (CD62L) and the integrin α4β7.

NF-κB/IκB PATHWAY

In resting lymphocytes, the transcription factor NF-κB forms a complex with IκB in the cytoplasm. Engagement of Toll receptors by microbes activates a cascade that leads ultimately to activation of the NF-κB kinase, NIK, and the formation of the dimer Iκk. Iκk phosphorylates IκB, resulting in its dissociation from NF-κB. NF-κB then enters the nucleus where it binds to (and activates) the promoters of various pro-inflammatory cytokines genes.

CROHN'S DISEASE

One of two idiopathic inflammatory bowel diseases that is characterized by chronic intestinal inflammation. The inflammatory lesions of Crohn's Disease can occur in any part of the gastrointestinal tract. By contrast, ulcerative colitis is typically confined to the colon.

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Nagler-Anderson, C. Man the barrier! strategic defences in the intestinal mucosa. Nat Rev Immunol 1, 59–67 (2001). https://doi.org/10.1038/35095573

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  • DOI: https://doi.org/10.1038/35095573

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