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  • Review Article
  • Published:

Regional specialization within the intestinal immune system

Nature Reviews Immunology volume 14, pages 667–685 (2014)Cite this article

Subjects

Key Points

  • The intestine is essential for life, and it is continuously exposed to foreign antigens and other environmental agents. Therefore, it comprises the largest compartment of the immune system, with substantial amounts of organized lymphoid tissue and large populations of scattered innate and adaptive effector cells.

  • Many studies of intestinal immunology have overlooked the fact that the intestine comprises several anatomically defined segments that each have distinct physiological roles and immunological components.

  • The immune system of the small intestine focuses on protecting the ability of the surface epithelium to digest and absorb foodstuffs by defending it from infection. The mechanisms include: IL-17- and IL-22-producing T cells and innate lymphoid cells; the production of antimicrobial peptides; and intraepithelial T cells with innate and cytolytic effector functions. Regulatory T cells help to prevent hypersensitivity reactions to dietary antigens.

  • The large intestine (colon) is not involved in digestion but is the reservoir for huge numbers of commensal microorganisms that are essential for health. The colonic immune system recognizes these microorganisms as potential hazards and keeps them 'at arms length' without expelling them. This involves the production of a thick mucus layer, the generation of IgA antibodies and the presence of large numbers of regulatory T cells.

  • These different aspects of immune function are served by distinct kinds of secondary lymphoid organs and are shaped by factors in the local environment, such as dietary components and bacterial metabolites.

  • Elucidating the factors that determine the anatomical compartmentalization of the intestinal immune system will improve our understanding of why intestinal diseases tend to occur at particular anatomical sites in the intestine.

Abstract

The intestine represents the largest compartment of the immune system. It is continually exposed to antigens and immunomodulatory agents from the diet and the commensal microbiota, and it is the port of entry for many clinically important pathogens. Intestinal immune processes are also increasingly implicated in controlling disease development elsewhere in the body. In this Review, we detail the anatomical and physiological distinctions that are observed in the small and large intestines, and we suggest how these may account for the diversity in the immune apparatus that is seen throughout the intestine. We describe how the distribution of innate, adaptive and innate-like immune cells varies in different segments of the intestine and discuss the environmental factors that may influence this. Finally, we consider the implications of regional immune specialization for inflammatory disease in the intestine.

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Figure 1: Anatomy of the intestinal mucosa and its immune apparatus.
Figure 2: Distribution of environmental factors along the length of the intestine.
Figure 3: Lymph drainage along the length of the mucosa.
Figure 4: The immune apparatus varies along the intestinal tract.

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Acknowledgements

The authors would like to thank A. Sasor and E. Toth at Skåne University Hospital, Sweden, for the intestinal section and endoscopy images, respectively. W.W.A. is supported by grants from the Swedish Medical Research Council, the Swedish National Health Service and a Sapere Aude senior researcher grant from the Danish Research Council. A.M.M is supported by grants from the Medical Research Council, UK, the Wellcome Trust and Tenovus Scotland.

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Authors and Affiliations

  1. Centre for Immunobiology, Institute of Infection, Immunity and Inflammation, University of Glasgow, Sir Graeme Davies Building, 120 University Avenue, Glasgow, G12 8TA, Scotland, UK

    Allan M. Mowat

  2. Department of Experimental Medical Science, Immunology Section, Lund University, BMC D14, Sölvegatan 19, Lund, S-221 84, Sweden

    William W. Agace

  3. Section of Immunology and Vaccinology, Danish Technical University Veterinary Institute, Bülowsvej 27, Copenhagen, DK-1870, Denmark

    William W. Agace

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  1. Allan M. Mowat
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Correspondence to Allan M. Mowat or William W. Agace.

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Glossary

Paneth cells

Specialized epithelial cells located just below the epithelial stem cells in the small intestinal crypts of Lieberkühn. They are a rich source of antimicrobial peptides that preserve crypt sterility and protect the epithelial stem cell niche.

Goblet cells

Specialized epithelial cells that produce mucus.

Submucosa

The layer of the intestine that is immediately below the mucosa and above the external muscle. Peyer's patches and colonic patches are located in the submucosa.

Coeliac disease

An inflammatory disorder of the duodenum and jejunum that is caused by immune responses to specific peptides that are found within the α-gliadin component of wheat gluten. Pathology includes the loss of villus architecture with reduced area of the surface epithelium, which leads to malabsorption.

Defensins

Small cationic proteins with antimicrobial properties that are produced by leukocytes and epithelial cells, such as Paneth cells.

Crohn's disease

An inflammatory bowel disease that is characterized by chronic transmural inflammation and associated granuloma formation. Pathology can affect all parts of the digestive tract, in particular, the colon and terminal ileum.

Follicle-associated epithelium

(FAE). A layer of columnar epithelial cells covering the surface of gut-associated lymphoid tissues such as Peyer's patches, the appendix and isolated lymphoid follicles. The FAE contains several immune cell populations and microfold cells.

Microfold cells

(M cells). Specialized epithelial cells found within the follicle-associated epithelium that covers gut-associated lymphoid tissues. M cells lack microvilli and an overlying glycocalyx, and they are specialized in the uptake of bacteria and other particulate antigens, transporting them to neighbouring antigen- presenting cells. They represent a major site of entry for many viral and bacterial intestinal pathogens.

Subepithelial dome

(SED). The area directly beneath the follicular- associated epithelium of gut-associated lymphoid tissues. It is rich in antigen-presenting cells and B cells.

Caecal patches

Areas of organized lymphoid tissue found in the submucosa of the caecum in mice that are thought to be equivalent to the human appendix and to be responsible for generating colon-homing IgA+ plasma cells. The removal of caecal patches can prevent experimental inflammatory bowel disease.

Colonic patches

Organized lymphoid tissues that are found in the submucosa of the colon. They contain both B cell and T cell areas, and develop before birth.

Solitary isolated lymphoid tissues

(SILTs). The collective term for small lymphoid follicle aggregates that are found in the mucosa of the intestine. They include both cryptopatches and more mature isolated lymphoid follicles.

Cryptopatches

Small organized areas of lymphoid tissue that are found in the wall of the intestine. Cryptopatches contain dendritic cells and lymphoid tissue inducer cells, and they are thought to be immature forms of isolated lymphoid follicles.

Isolated lymphoid follicles

(ILFs). Mature lymphoid aggregates that are found in the mucosa. They primarily consist of B cells, dendritic cells and innate lymphoid cells, and they are covered by a follicle-associated epithelium. ILFs are thought to have a role in initiating local IgA responses and they are found throughout the intestine.

Mesenteric lymph nodes

(MLNs). The series of lymph nodes draining the small intestine and upper colon. Human MLNs are found throughout the intestinal mesentery, whereas in the mouse, they consist of a string of four or five lymph nodes.

Caudal lymph node

A lymph node found in the abdomen near the bifurcation of the aorta that is responsible for draining lymph from the descending colon and rectum.

Innate lymphoid cells

(ILCs). A relatively recently identified population of non-T, non-B lymphocytes that are believed to have a central role in early innate immune responses in the intestinal mucosa. They have been subdivided into three main groups according to whether they express T helper 1 (TH1)-type, TH2-type or TH17-type transcription factors and cytokines.

Segmented filamentous bacteria

(SFB). Commensal bacteria that are found as part of the normal microbiota in certain mouse facilities. Currently unculturable, these anaerobes colonize the terminal ileum of rodents, adhering to ileal enterocytes, and they have a major impact on the development and composition of immune cell populations in the small intestine.

Mucosal-associated invariant T cells

(MAIT cells). Cells that express a semi-invariant T cell receptor (TCR) comprising the canonical TCR Vα7.2 and Jα33 in humans, and Vα19 and Jα33 in mice. They are predominantly found in the human jejunum and are believed to recognize vitamin B metabolites presented by MHC class I-related protein.

Invariant natural killer T cell

(iNKT cell). T cells that express an invariant form of the αβ T cell receptor that recognizes glycolipid antigens presented by the CD1d molecule. They produce cytokines at an early stage in immune responses and may contribute to intestinal inflammation.

Lymphotoxin-β receptor–Fc fusion protein

A fusion protein comprising the lymphotoxin-β receptor linked to the Fc portion of an immunoglobulin heavy chain. When given to pregnant mice, it prevents the development of Peyer's patches and other components of the gut-associated lymphoid tissue in the offspring by specifically blocking access of the α1β2 isoform of lymphotoxin to the LTβ receptor.

Plasmacytoid DCs

(Plasmacytoid dendritic cells; pDCs). A population of dendritic cells with the appearance of plasma cells and a specialized ability to produce type I interferons in response to viruses and Toll-like receptor ligation, but little or no antigen presentation activity.

Ulcerative colitis

One of the two major forms of human inflammatory bowel disease. It presents as a continuous area of inflammation that is restricted to the large intestine and is characterized by erythema, superficial ulceration and pseudopolyps.

Dysbiosis

An imbalance in the composition of the microbial species that are normally found in the intestine. It is associated with alterations in immune function and susceptibility to inflammatory diseases, allergies and metabolic conditions.

Dextran sodium sulphate

(DSS). Sodium salt of dextran that causes an acute colitis in rodents when administered orally.

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Mowat, A., Agace, W. Regional specialization within the intestinal immune system. Nat Rev Immunol 14, 667–685 (2014). https://doi.org/10.1038/nri3738

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