Anatomy

The immune system associated with the small intestine is currently described according to two compartments: (i) the inducing sites, named the gut associated lymphoid tissue (GALT), consisting of organized aggregated lymphoid tissue, scattered small nodules, Peyer's patches (PPs), and mesenteric lymph nodes (MLN); and (ii) the effector sites, i.e., the lamina propria tissue where numerous mature B and T small lymphocytes (60% CD4 + T cells), plasma cells of which about 90% synthesize IgA are present, and the epithelium richly endowed with intra-epithelial lymphocytes (IEL) (CD8 + T cells) present between the tight junctions of some enterocytes (Fig. 2) (30-32,35).

PPs are the first important inductive sites. They are macroscopic lymphoid aggregates that are found in the submucosa along the length of the small intestine. They consist of large B-cell follicles and intervening T-cell areas which are separated from the single layer of intestinal epithelial cells, known as the follicle-associated epithelium (FAE), by the subepithelial dome region where APCs are numerous (31). An important feature of the FAE is the presence of microfold (M) cells, which, in contrast to enterocytes, lack the surface microvilli, the normal thick layer of mucus, and cellular lysosomes. Thus, M cells are distinctive epithelial cells that occur only in the FAE. It is believed that they play a central role in the initiation of mucosal immune responses by transporting Ags, and microorganisms, to the underlying organized lymphoid tissue within the mucosa.

© Peyer's Patch Villus

© Peyer's Patch Villus

Lamina Propria Galt
Figure 2 Schematic representation of the intestinal immune system. Abbreviations: GALT, gut-associated lymphoid tissue; IEL, intraepithelial lymphocytes; LP, lamina propria; MLN, mesenteric lymph nodes; PP, Peyer's patches.

Most of the mature cells found in the effector sites, T cells, plasma cells, epithelium CD8 a-b thymus-dependent IEL, derive from PPs. After oral Ag stimulation, the Ag-activated immature T and B cells present in PPs leave the PP, and migrate into the systemic compartment via the MLN, and the lymph, then enter the bloodstream via the thoracic duct. Subsequently the expression of a4b7 integrin, expressed at the surface of cells, allows them to bind the gut-specific vascular addressin, MadCAM-1, which is expressed at high levels by the vasculature of mucosal surfaces, inducing the cells to migrate across the endothelium into the lamina propria. Within the intestinal lamina propria, B cells differentiate into IgA-secreting plasma cells with a half-life of about 4V2 days, and most of the T cells undergo apoptosis. This fact has been suggested to be important to maintain the gut homeostasis preventing immune responses to luminal Ags (36). This cellular traffic, between the PP and lamina propria, has been particularly described for IgA plasmocytes. After antigenic stimulation at the PP, B cells undergo Ig class switching from expression of IgM to IgA which is under the influence of several factors, including cytokines, TGF-b, IL-4, and IL-10, and cellular signals delivered by DC and T cells present in PPs. After returning to the lamina propria, IgA plasmocytes synthesize and assemble two IgA units and the J chain. Then, a polymeric-Ig receptor (pIgR) expressed by enterocytes allows selective transcytosis through the epithelial cells, and dimeric IgA are excreted in the lumen associated with the secretory component, a protein derived from the pIgR, which confers to sIgA interesting properties such as resistance to proteolytic enzymes present in the intestinal lumen (37).

The physiological significance of the entero-enteric cell circulation is important. The induction of an immune response at a PP level propagates distally relative to the induction site, not only throughout the intestine but also to other mucosa. It has been shown that T and B cells, which have been activated in the GALT, are able to reach other mucosal surfaces, which together compose the mucosa-associated lymphoid tissue (MALT; vagina, breast during pregnancy and lactation, respiratory tract) by the way of homing receptors. This is known as the "common immune system of the mucosa." The cycle also shows that there are relationships between the IIS and systemic compartment, even though they have, as yet, not been fully elucidated.

The APCs play a crucial role in the initiation and regulation of the immune responses, and are present in all the parts of IIS. In PPs we found immature DCs located in close proximity to M cells, which have the capacity to migrate into the interfollicular areas of the PP (T areas) and also via the lymphatic to T-cell areas of MLN, thereby stimulating T cells in both locations. In all these locations where T cells are stimulated by a given gut Ag, the resulting blasts have the capacity to move via the lymph to the thoracic duct and the blood to finally home in the gut wall. Ag-specific effector and memory cells thereby become disseminated along the whole gut wall, in the lamina propria, and the epithelium.

Several and unusual subsets of DCs have been described in the murine PP. They are located either in the subepithelial dome (CD11b + /CD8 —), or in the intrafollicular regions (CD11b — /CD8C) or at both sites (CD11b — /CD8 —) (38). It has been described in mice that CD11b + /CD8 — DC, present in the subepithelial dome of PP, have unusual functional characteristics and differ from their peripheral counterparts. Upon antigenic stimulation, they secrete IL-10 and induce naive T cells to differentiate into Th2 with IL-4 and IL-10 production (38). In contrast, in the spleen, the same DC subset secretes IL-12 after antigenic stimulation under the same experimental conditions, and consequently drives the immune response to a Th1 orientation with production of IFN-g. However the authors showed that the double negative population CD11b —/CD8— of DCs, is capable of secreting Il-12 upon recognition of microbial stimuli. These functional differences in the different PP DC populations may come from the type of Ag stimulation. Indeed, T cells in PP of mice immunized orally with live Salmonella typhimurium secrete large quantities of IFN-g (39). In these studies, it also seems to be important to consider the intestinal site from which PPs originate. In fact recent studies have shown that the presence of intestinal bacteria in the ileum influence the cytokine profile secreted by DCs in PPs (40).

DCs are also found in the intestinal villi at the subepithelial level in lamina propria. When activated, they can penetrate the epithelium, and send dendrites to the epithelium surface, thus being able to directly sample luminal Ags and to present them to IEL and lamina propria lymphocytes (31,35). Unusual subsets of DCs are also found, including some that are similar to the IL-10 inducing DCs that have been described in PPs. This characteristic constitutes a particularity of DCs present both in PPs, lamina propria, and epithelium, with functional consequences as presented below for the section on oral tolerance.

Another characteristic of the IIS is the presence of large numbers of activated memory CD4+ and CD8 + T cells throughout the lamina propria, expressing the chemokine receptor CCR5, probably because of the continuous exposure to environmental antigens (41). By contrast, the majority of CD4 + T cells in the peripheral blood and nodes are naive T cells (lack of CCR5 expression). It has been reported that PP contains naive T cells, expressing chemokine receptor CXCR4, but also activated and memory T cells, a phenomenon which is not found in other inductive lymphoid tissue such as MLN or peripheral lymph nodes (42). The reasons for this are unknown.

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