REVIEWS ANATOMICAL BASIS OF TOLERANCE AND IMMUNITY TO INTESTINAL ANTIGENS Allan McI. Mowat 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. COELIAC DISEASE The intestinal immune system is the largest and most the immune system, as it partly results from inherent A chronic inflammatory complex part of the immune system. Not only does it properties of the antigen and associated adjuvants. condition of the upper small encounter more antigen than any other part of the Nevertheless, it has been proposed that there are also intestine in humans that is body, but it must also discriminate clearly between specific features of mucosal tissues that favour the caused by immunological hypersensitivity to the α-gliadin invasive organisms and harmless antigens, such as food induction of tolerance, the production of immunoglob- component of wheat gluten. proteins and commensal bacteria. Most human ulin A antibodies and, to a lesser extent, T helper 2 It is often found in infants after 4 pathogens enter the body through a mucosal surface, (TH2)-cell responses . Several features of mucosal tis- the introduction of solid foods. such as the intestine, and strong immune responses are sues might contribute to these effects4, including a It causes severe villus atrophy, required to protect this physiologically essential tissue. unique ontogeny and anatomical patterning, special- which can lead to malabsorption and malnutrition if gluten- In addition, it is important to prevent further dissemi- ized cells and organs that are involved in the uptake of containing foods are not removed nation of such infections. By contrast, active immunity antigen, distinctive subsets of antigen-presenting cells from the diet. against non-pathogenic materials would be wasteful, (APCs) and several unusual populations of B and and hypersensitivity responses against dietary antigens T cells. In addition, the migration of lymphocytes to the or commensal bacteria can lead to inflammatory disor- intestine is controlled by a series of unique adhesion ders such as COELIAC DISEASE and CROHN’S DISEASE, respec- molecules and chemokine receptors. In this review, tively. As a result, the usual response to harmless gut I discuss the anatomical factors which determine the antigens is the induction of local and systemic immuno- special nature of small intestinal immune responses, logical tolerance, known as oral tolerance1,2. In addition and the unique processes and cells involved in the to its physiological importance, this phenomenon can be uptake and presentation of antigen to T cells in the gut. exploited for the immunotherapy of autoimmune and In particular, I focus on the local factors that determine inflammatory diseases3, but it is also an obstacle to the the behaviour of APCs and T cells in the gut and discuss Department of Immunology development of recombinant oral vaccines. For these recent evidence that challenges the conventional dogma and Bacteriology, reasons, there is great interest in the processes that that Peyer’s patches are the only site for the initiation of Western Infirmary, determine the immunological consequences of oral mucosal immunity and tolerance. Glasgow G11 6NT, UK. administration of antigen. I focus on the small intestine, as this tissue has been e-mail: a.m.mowat@ clinmed.gla.ac.uk To some extent, this discrimination between harm- studied in most detail and it contains the largest pro- doi:10.1038/nri1057 ful and harmless antigens also occurs in other parts of portion of immune cells in the gut. However, the reader NATURE REVIEWS | IMMUNOLOGY VOLUME 3 | APRIL 2003 | 331 © 2003 Nature Publishing Group REVIEWS CROHN’S DISEASE should be aware that each compartment of the intestine, p52–RelB heterodimeric subunit of nuclear factor (NF)- A form of chronic inflammatory from the oro-pharynx to the stomach and to the rec- κB, mediated by signalling through the lymphotoxin-β bowel disease that can affect the tum, has its own specializations, which might have indi- receptor (LTβR) that is expressed by vascular-cell adhe- entire gastrointestinal tract, but vidual effects on immune regulation in response to local sion molecule 1 (VCAM1)+ mesenchymal cells. The p55 is commonest in the colon and terminal ileum. It is antigens. form of the tumour-necrosis factor receptor (TNFRp55) characterized by transmural might also have an accessory role in the development of inflammation, strictures and GALT anatomy and intestinal immune responses Peyer’s patches6–11. granuloma formation, and is The gut-associated lymphoid tissue (GALT) can be Mature Peyer’s patches consist of collections of large believed to result from an abnormal T-cell-mediated divided into effector sites, which consist of lymphocytes B-cell follicles and intervening T-cell areas. The lym- immune response to commensal scattered throughout the epithelium and lamina propria phoid areas are separated from the intestinal lumen by a bacteria. of the mucosa, and organized tissues, that are responsi- single layer of columnar epithelial cells, known as the ble for the induction phase of the immune response follicle-associated epithelium (FAE), and a more diffuse BRUSH BORDER (FIGS 1,2). These are the Peyer’s patches and mesenteric area immediately below the epithelium, known as the The surface layer of the normal small intestine that is comprised lymph nodes (MLNs), as well as smaller, isolated lym- subepithelial dome (SED) (FIG. 2). The FAE differs from of small microvilli coated in a phoid follicles, which have the appearance of micro- the epithelium that covers the villus mucosa, as it has rich glycocalyx of mucus and scopic Peyer’s patches and are distributed throughout lower levels of digestive enzymes and a less pronounced other glycoproteins. The 5 the wall of the small and large intestines . BRUSH BORDER, also it is infiltrated by large numbers of microvilli contain many of the digestive enzymes and B cells, T cells, macrophages and dendritic cells (DCs). transporter systems that are Peyer’s patches. The Peyer’s patches are macroscopic The most notable feature of the FAE is the presence of involved in the metabolism and lymphoid aggregates that are found in the submucosa microfold (M) cells, which are specialized enterocytes uptake of dietary materials. The along the length of the small intestine (FIG. 2). In mice, that lack surface microvilli and the normal thick layer of brush border provides a large the pre-natal development of Peyer’s patches is distinct mucus (FIG. 2). M cells differentiate from enterocytes surface area for absorption. α β from that of peripheral lymphoid tissues, being under the influence of membrane-bound LT 1 2 that is α β 12–14 induced by the production of lymphotoxin- 1 2 present on local lymphoid cells, mainly B cells .They α β – + (LT 1 2) by recirculating CD3 CD4 progenitor cells bind invasive pathogens, such as Salmonella, Shigella, that respond to the local expression of interleukin-7 Yersinia and reoviruses, and other particulate antigens. (IL-7). The entry of CD3–CD4+ progenitor cells into the developing Peyer’s patches also uniquely requires Mesenteric lymph nodes. The MLNs are the largest expression of the chemokine receptor CXCR5. The lymph nodes in the body. Their development is distinct α β effects of LT 1 2 involve the selective activation of the from that of both Peyer’s patches and peripheral lymph Scattered lymphoid cells — effector sites Intraepithelial lymphocyte Villus Epithelium Organized tissues — induction sites M cell Intestinal SED lumen Follicle Peyer's TDA patch Lamina Lymphatic propria drainage Crypt Afferent lymphatic Mesenteric lymph node Figure 1 | Schematic representation of the lymphoid elements of the intestinal immune system. The organized tissues of the Peyer’s patches and mesenteric lymph nodes (MLNs) are involved in the induction of immunity and tolerance, whereas the effector sites are scattered throughout the lamina propria and epithelium of the mucosa. Both the Peyer’s patches and villus lamina propria are drained by afferent lymphatics that go to the MLNs. SED, subepithelial dome; TDA, thymus-dependent area. 332 | APRIL 2003 | VOLUME 3 www.nature.com/reviews/immunol © 2003 Nature Publishing Group REVIEWS ab FAE Dome LP Peyer's patch c Peyer's patch M cell Figure 2 | Histological appearance of Peyer’s patches and intestinal mucosa. a | Normal small intestine showing the characteristic architecture of finger-like villi that are covered by a single layer of columnar epithelial cells, which encloses the central lamina propria (LP). b | Peyer’s patches are aggregates of secondary lymphoid tissue present in the submucosa of the small intestine. They are separated from the lumen by the follicle-associated epithelium (FAE), which is comprised of columnar epithelial cells and also contains microfold (M) cells, dendritic cells (DCs), T cells, B cells and macrophages. The area immediately beneath the FAE (‘dome’) is rich in DCs. c | Scanning-electron micrographs of Peyer’s patches and FAE. At low magnification (left), the dome shape of the Peyer’s patch protrudes between villi into the lumen of the intestine. At higher magnification (centre and right), M cells can be seen as epithelial cells with surface microfolds rather than the microvilli that are seen on the surrounding conventional enterocytes. Antigen is taken up preferentially through M cells (right). Images reproduced from REF.4, with permission from Blackwell Publishing Ltd. nodes, as it is relatively unaffected by the absence of most Induction of intestinal immune responses. It has been of the factors that are involved in the ontogeny of these assumed for many years that M cells provide the main, if α β β other organs, including TNF,TNFR, LT 1 2 and LT R.