Dendritic Cells Mucosa Intestine Treg Cell

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Bacterial PAMP

Bacterial PAMP

FIGURE 13-2 Mechanism of regulation of innate immune responses in the intestinal mucosa. Pattern recognition receptor expression and function in intestinal epithelial cells and lamina propria DCs minimize inflammatory responses to commensal bacteria in the lumen but promote responses to microbes that traverse the barrier and enter the lamina propria. Top, Pattern recognition receptors that recognize bacterial flagellin are compartmentalized in the cytosol (NLR) or basal membrane (TLR5) of intestinal epithelial cells but not on the apical/lumen membrane. Bottom,TLR4, which recognizes bacterial lipopolysaccharides, is expressed at low levels on intestinal epithelial cells and lamina propria DCs. TLR signaling does not induce inflammatory gene expression in lamina propria DCs because of more dominant effect of intracellular regulators of TLR signal transduction, such as TOLLIP and IRAK-M, compared with conventional DCs in other tissues.

Innate receptors for bacterial PAMPS expressed in cytoplasm and on basolateral membrane, but not on lumenal surface

Dendritic cells in lamina propria express low levels of TLR

FIGURE 13-2 Mechanism of regulation of innate immune responses in the intestinal mucosa. Pattern recognition receptor expression and function in intestinal epithelial cells and lamina propria DCs minimize inflammatory responses to commensal bacteria in the lumen but promote responses to microbes that traverse the barrier and enter the lamina propria. Top, Pattern recognition receptors that recognize bacterial flagellin are compartmentalized in the cytosol (NLR) or basal membrane (TLR5) of intestinal epithelial cells but not on the apical/lumen membrane. Bottom,TLR4, which recognizes bacterial lipopolysaccharides, is expressed at low levels on intestinal epithelial cells and lamina propria DCs. TLR signaling does not induce inflammatory gene expression in lamina propria DCs because of more dominant effect of intracellular regulators of TLR signal transduction, such as TOLLIP and IRAK-M, compared with conventional DCs in other tissues.

inflammatory reactions that would compromise the mucosal barrier. Nowhere else in the body is there such an extensive commitment of the immune system to maintaining tolerance to foreign antigens. A major mechanism for controlling responses in the gut is the activation of regulatory T cells (Treg), and some subsets of Treg are more abundant in mucosa-associated lymphoid tissues (MALT) than in other lymphoid organs.

We will now discuss the special features of adaptive immunity in the gastrointestinal system, including anatomic organization, antigen sampling, lymphocyte homing and differentiation, and antibody delivery to the lumen.

The Functional Anatomy of the Adaptive Immune System in the Gastrointestinal Tract

In this section, we will discuss the anatomic organization of cells within the intestines and the relationship of this organization to how adaptive immune responses are initiated, carried out, and regulated. In general terms, the functional anatomy of the adaptive immune system in the gut has evolved to effectively deal with the conditions we emphasized earlier of abundant commensal microbes and rare pathogens just outside an epithelial barrier of enormous surface area.

Adaptive immune responses in the gut are initiated in discretely organized collections of lymphocytes and antigen-presenting cells closely associated with the mucosal epithelial lining of the bowel and in mesenteric lymph nodes (see Fig. 13-1). Naive lymphocytes are exposed to antigens in these sites and differentiate into effector cells. These gut-associated lymphoid tissues adjacent to the mucosal epithelium are sometimes referred to as GALT, which is the gastrointestinal version of MALT, although the terms are often used interchangeably. Up to 30% of the lymphocytes in the body are found in the GALT. The most prominent GALT structures are Peyer's patches, found mainly in the distal ileum, and smaller aggregates of lymphoid follicles or isolated follicles in the appendix and colon. Peyer's patches have the structure of lymphoid follicles, with germinal centers containing B lymphocytes, follicular helper T cells, follicular dendritic cells (FDCs), and macrophages. The germinal centers in the follicles are surrounded by IgM- and IgD-expressing naive follicular B cells. A region called the dome is located between the follicles and the overlying epithelium and contains B and T lymphocytes, DCs, and macrophages. Between the follicles are T cell-rich parafollicular areas, similar to lymph nodes, but overall, the ratio of B cells to T cells in GALT is about five times higher than in lymph nodes. Also in distinction from lymph nodes, GALT structures are not encapsulated, and there are routes of antigen delivery to these structures that are independent of lymphatics. Development of both aggregates of follicles, such as Peyer's patches, and isolated

FIGURE 13-3 M cells in the small intestine. M cells are specialized intestinal epithelial cells found in the small bowel epithelium overlying Peyer's patches and lamina propria lymphoid follicles (A). Unlike neighboring epithelial cells with tall microvillous borders and primary absorptive functions, M cells have shorter villi (B) and engage in transport of intact microbes or molecules across the mucosal barrier into gut-associated lymphoid tissues, where they are handed off to DCs (C). (Electron micrograph from Corr SC, CC Gahan, and C Hill. M-cells: origin, morphology and role in mucosal immunity and microbial pathogenesis. FEMS Immunology and Medical Microbiology 52:2-12, 2008.)

FIGURE 13-3 M cells in the small intestine. M cells are specialized intestinal epithelial cells found in the small bowel epithelium overlying Peyer's patches and lamina propria lymphoid follicles (A). Unlike neighboring epithelial cells with tall microvillous borders and primary absorptive functions, M cells have shorter villi (B) and engage in transport of intact microbes or molecules across the mucosal barrier into gut-associated lymphoid tissues, where they are handed off to DCs (C). (Electron micrograph from Corr SC, CC Gahan, and C Hill. M-cells: origin, morphology and role in mucosal immunity and microbial pathogenesis. FEMS Immunology and Medical Microbiology 52:2-12, 2008.)

follicles in the gut lamina propria requires lymphoid tissue inducer cells, which express the RORYT transcription factor and produce the cytokine lymphotoxin-P (LTp).

A major pathway of antigen delivery from the lumen to the GALT is through specialized cells within the gut epithelium called microfold (M) cells (Fig. 13-3). M cells are located in regions of the gut epithelium called follicle-associated or dome epithelium that overlie the domes of Peyer's patches and other GALT structures. Although M cells and the more numerous epithelial cells with absorptive function likely arise from a common epithelial precursor, the M cells are distinguishable by a thin glycocalyx, their relatively short, irregular microvilli (referred to as microfolds), and large fenestrations in their membranes, all features that enhance the uptake of antigens from the gut lumen. The main function of M cells is transcellular transport of various substances from the lumen of the intestine across the epithelial barrier to underlying antigen-presenting cells. M cells take up luminal contents efficiently and in various ways, including phagocytosis in a manner similar to macrophages, and either clathrin-coated vesicular or fluid-phase endocytosis. These pathways enable uptake of whole bacteria, viruses, and soluble microbial products. Unlike macrophages or DCs, M cells do not engage in extensive processing of the substances they take up, but rather they move the particles and molecules through endocytic vesicles across the cytosol and deliver them by exocytosis at the basolateral membrane to DCs in the dome regions of underlying GALT structures. Although M cells play an important role in protective immunity to luminal microbes, some microbes have evolved to take advantage of M cells as a route of invasion through the mucosal barrier. The best described example of this is Salmonella typhimurium, similar to the human pathogen S. typhi that causes

Clostridium Poultry Intestine

FIGURE 13-4 DCs in the intestinal mucosa. There are several different subsets of DCs constitutively present in the intestinal mucosa that are defined by cell surface molecules and function. Two such subsets are shown that are also present in other mucosal tissues. A, Antigen-sampling DCs extend dendritic processes between intestinal epithelial cells into the lumen to sample antigens and then migrate to mesenteric lymph nodes, where they initiate activation and differentiation of proinflammatory effector T cells. These DCs express the CD11b integrin chain and the CX3CR1 chemokine receptor. B, Other DCs present in the lamina propria, which express the integrin CD103, present antigens to naive T cells and induce their differentiation of regulatory T cells, in part by secreting TGF-P and retinoic acid (RA). The regulatory function of these DCs depends on factors secreted by intestinal epithelial cells.

FIGURE 13-4 DCs in the intestinal mucosa. There are several different subsets of DCs constitutively present in the intestinal mucosa that are defined by cell surface molecules and function. Two such subsets are shown that are also present in other mucosal tissues. A, Antigen-sampling DCs extend dendritic processes between intestinal epithelial cells into the lumen to sample antigens and then migrate to mesenteric lymph nodes, where they initiate activation and differentiation of proinflammatory effector T cells. These DCs express the CD11b integrin chain and the CX3CR1 chemokine receptor. B, Other DCs present in the lamina propria, which express the integrin CD103, present antigens to naive T cells and induce their differentiation of regulatory T cells, in part by secreting TGF-P and retinoic acid (RA). The regulatory function of these DCs depends on factors secreted by intestinal epithelial cells.

typhoid fever. M cells express specific lectins that allow these bacteria to specifically bind and be internalized. The bacteria are cytotoxic to the M cells, leading to gaps in the epithelium that promote invasion of more organisms. M cell lectins may also promote infection by certain enteric viruses.

Microbial antigens in the gut lumen can be sampled by lamina propria DCs that extend cytoplasmic processes between the intestinal epithelial cells and by Fc receptor-dependent uptake of IgG opsonized antigens by the epithelial cells (Fig. 13-4). Antigen-sampling DCs are numerous in certain regions of the intestine, especially the terminal ileum, where they extend dendrites through the junctions between adjacent epithelial cells, apparently without disrupting the tight junctions. These antigen-sampling DCs belong to a subset of mucosal DCs that promote effector T cell responses, which we will discuss later in the chapter. Unlike M cells, these DCs are capable of processing and presenting protein antigens to T cells within the GALT. Antigens in the lumen that have been opsonized by antibodies can be delivered to the GALT by Fc receptor-mediated pathways. There is evidence from mouse studies that IgG-opsonized antigens, such as bacterial flagellin, can be transported across the gut epithelium through the neonatal Fcy receptor (FcRn, see Chapter 12) and passed on to DCs in the GALT, leading to T cell responses to the antigens.

Mesenteric lymph nodes collect lymph-borne antigens from the small and large bowel and are sites of differentiation of effector and regulatory lymphocytes that home back to the lamina propria. There are 100 to

150 of these lymph nodes located between the membranous layers of the mesentery. Mesenteric lymph nodes serve some of the same functions as GALT, including differentiation of B cells into dimeric IgA-secreting plasma cells and the development of effector T cells as well as regulatory T cells. The cells that differentiate in the mes-enteric lymph nodes in response to bowel wall invasion by pathogens or commensals often home to the lamina propria. We will discuss imprinting of homing properties of lymphocytes activated in mesenteric lymph nodes later.

Lingual and palatine tonsils are nonencapsulated lymphoid structures located beneath stratified squamous epithelial mucosa in the base of the tongue and oropharynx, respectively, and are sites of immune responses to microbes in the oral cavity. These tonsils, together with nasopha-ryngeal tonsils, form a ring of lymphoid tissues called Waldeyer's ring. The bulk of the tonsillar tissue is composed of lymphoid follicles, usually with prominent germinal centers. There are multiple narrow and deep invaginations of the surface squamous epithelium, called crypts, that grow into the follicular tissue. Although these tonsils are often considered part of the GALT, they are distinct in that they are separated from the microbe-rich oral cavity by multiple layers of squamous epithelial cells rather than the single epithelial cell layer of the gut. The mechanism of antigen sampling from oral cavity microbes oVitamin A

Peyer Patch
Peyer's patch or mesenteric lymph node

FIGURE 13-5 Homing properties of intestinal lymphocytes. The gut-homing properties of effector lymphocytes are imprinted in the lymphoid tissues where they have undergone differentiation from naive precursors. DCs in gut-associated lymphoid tissues, including Peyer's patches and mesenteric lymph nodes, are induced by thymic stromal lymphopoietin (TSLP) and other factors to express retinaldehyde dehydrogenase (RALDH), which converts dietary vitamin A into retinoic acid. When naive B or T cells are activated by antigen in GALT, they are exposed to retinoic acid produced by the DCs, and this induces the expression of the chemokine receptor CCR9 and the integrin a4|37 on the plasma cells and effector T cells that arise from the naive lymphocytes. The effector lymphocytes enter the circulation and home back into the gut lamina propria because the chemokine CCL25 (the ligand for CCR9) and the adhesion molecule MadCAM (the ligand for a4p7) are displayed on lamina propria venular endothelial cells.

is not well described; the crypts are possible sites where this may happen. Nonetheless, the lingual and palatine tonsils respond to infections of the epithelial mucosa by significant enlargement and vigorous, mainly IgA, antibody responses. Typical infections that are associated with tonsillar enlargement, usually in children, are caused by streptococci and the Epstein-Barr virus.

Effector lymphocytes that are generated in the GALT and mesenteric lymph nodes are imprinted with selective integrin- and chemokine receptor-dependent gut-homing properties, and they circulate from the blood back into the lamina propria of the gut (Fig. 13-5). Both IgA-secreting B cells and effector T cells acquire the gut-homing phenotype. Thus, the effector arm of the gastrointestinal immune system depends on a large number of antibody-secreting cells and T cells that recirculate back into the lamina propria and respond rapidly to pathogens. The major integrin on gut-homing B and T lymphocytes is a4p7, which binds to the MadCAM-1 protein expressed on postcapillary venular endothelial cells in the gut lamina propria. Gut homing also requires the chemokine receptor CCR9 on the B and T lymphocytes and its chemokine ligand CCL25, which is produced by intestinal epithelial cells. The combined expression of MadCAM-1 and CCL25 is restricted to the gut. Homing of IgA-producing cells to the colon also requires CCR10 expression and the chemokine CCL28, but this is not a gut-specific pathway because CCL28 is expressed by epithelial cells in other mucosal tissues, such as the lung and genitourinary tract. Blocking monoclonal antibodies specific for the a4 chain of a4p7 have been used to treat patients with inflammatory bowel disease on the basis of the knowledge that effector T cells use this integrin to enter gut tissues in this disease. (We will discuss inflammatory bowel disease later in the chapter.)

The gut-homing phenotype of IgA-producing cells and effector T cells is imprinted by DCs and the action of reti-noic acid during the process of T cell activation (see Fig. 13-5). In addition to promoting naive T cell differentiation into effector T cells and naive B cell differentiation into IgA antibody-secreting cells, discussed later in the chapter, DCs in GALT and mesenteric lymph nodes also provide signals that lead to the expression of a4p7 and CCR9 on these effector cells. The induction of these homing molecules depends on secretion of retinoic acid by the DCs, although the mechanisms are not well understood. The selective induction of gut-homing cells in the gut lymphoid tissues is explained by the fact that gut lymphoid tissues are exposed to dietary vitamin A, and DCs in GALT and mesenteric lymph nodes express retinal dehydrogenases (RALDH), the enzyme needed for retinoic acid synthesis from vitamin A, whereas DCs in other tissues do not. In addition, intestinal epithelial cells also express RALDH and can synthesize retinoic acid. Consistent with these properties of the intestinal humoral immune system, it is known that oral vaccination not only favors the expansion of IgA-producing B cells, compared with intradermal immunization, but that oral vaccines also induce higher levels of a4p7 on B cells.

The lamina propria contains diffusely distributed effector lymphocytes, DCs, and macrophages and is the site of the effector phase of gastrointestinal adaptive immune responses. As discussed before, effector lymphocytes generated in Peyer's patches, other GALT structures, and mesenteric lymph nodes home back into the lamina propria. In this location, T cells can respond to invading pathogens, and B cells can secrete antibodies that are transported into the lumen and neutralize pathogens before they invade.

Humoral Immunity in the Gastrointestinal Tract

Humoral immunity in the gut is dominated by production of secretory IgA in the GALT and transport of the antibody across the mucosal epithelium into the lumen.

Smaller but significant quantities of IgG and IgM are also secreted into the gut lumen. Within the lumen, IgA, IgG, and IgM antibodies bind to microbes and toxins and neutralize them by preventing their binding to receptors on host cells. This form of humoral immunity is sometimes called secretory immunity and has evolved to be particularly prominent in mammals. Antibody responses to antigens encountered by ingestion are typically dominated by IgA, and secretory immunity is the mechanism of protection induced by oral vaccines such as the polio vaccine. Several unique properties of the gut environment result in selective development of IgA-secreting cells that either stay in the gastrointestinal tract or, if they enter the circulation, home back to the lamina propria of the intestines. The result is that IgA-secreting cells efficiently accumulate next to the epithelium that will take up the secreted IgA and transport it into the lumen.

IgA is produced in larger amounts than any other antibody isotype. It is estimated that a normal 70-kg adult secretes about 2 g of IgA per day, which accounts for 60% to 70% of the total production of antibodies. This tremendous output of IgA is because of the large number of IgA-producing plasma cells in the GALT, which by some estimates amount to about 1010 cells per meter of bowel (Fig. 13-6). Because IgA synthesis occurs mainly in mucosal lymphoid tissue and transport into the mucosal lumen is efficient, this isotype constitutes less than one quarter of the antibody in plasma and is a minor component of systemic humoral immunity compared with IgG and IgM.

The dominance of IgA production by intestinal plasma cells is due in part to selective induction of IgA isotype switching in B cells in GALT and mesenteric lymph nodes. IgA class switching in the gut can occur by T-dependent and T-independent mechanisms (Fig. 13-7). In both cases, the molecules that drive IgA switching include both soluble cytokines and membrane proteins on other cell types that bind to signaling receptors on B cells (see Chapter 11). TGF-P is required for IgA isotype switching in the gut as well as in other mucosal compartments, and this cytokine is produced by intestinal epithelial cells and DCs in GALT. Furthermore, GALT DCs express the avp8 integrin, which is required for activation of TGF-p. Several molecules that promote IgA class switching are

FIGURE 13-6 IgA-secreting plasma cells in the intestine.

The abundance of IgA-producing plasma cells (green) in colon mucosa compared with IgG-secreting cells (red) is shown by immunofluorescence staining. IgA that is being secreted can be seen as green cytoplasm in the crypt epithelial cells. (From Brandtzaeg P. The mucosal Immune system and its integration with the mammary glands. The Journal of Pediatrics 156[Suppl 1]:S8-S16, 2010.)

FIGURE 13-6 IgA-secreting plasma cells in the intestine.

The abundance of IgA-producing plasma cells (green) in colon mucosa compared with IgG-secreting cells (red) is shown by immunofluorescence staining. IgA that is being secreted can be seen as green cytoplasm in the crypt epithelial cells. (From Brandtzaeg P. The mucosal Immune system and its integration with the mammary glands. The Journal of Pediatrics 156[Suppl 1]:S8-S16, 2010.)

expressed by intestinal epithelial cells or GALT DCs in response to TLR signaling, and the commensal bacteria in the gut lumen produce the ligands that bind to the relevant TLRs. For example, T-independent IgA and IgG switching requires binding of the TNF family cytokine APRIL to the TACI receptor on B cells, and intestinal epithelial cells produce APRIL in response to TLR ligands made by commensal bacteria. Intestinal epithelial cells also produce thymic stromal lymphopoietin (TSLP) in response to TLR signals, and TSLP stimulates additional APRIL production by GALT DCs. TLR ligands made by commensal bacteria in the gut also increase expression of inducible nitric oxide synthase in DCs, leading to nitric oxide production. Nitric oxide is thought to promote both T-dependent and T-independent IgA class switching, in part because nitric oxide enhances TGF-P signaling in B cells and also synthesis of APRIL by GALT DCs. Finally, intestinal B cell IgA production is at least partly dependent on the vitamin A metabolite all-trans retinoic acid, which is made by intestinal epithelial cells and GALT DCs, although the mechanisms by which retinoic acid promotes IgA production are not known. Retinoic acid is also important in B cell homing to the gut, as we discussed earlier. There is an abundance of many of these molecules within the GALT and mesenteric lymph nodes compared with nonmucosal lymphoid tissues such as spleen and skin-draining lymph nodes, largely accounting for the propensity of B cells in the GALT to switch to IgA production.

The dominance of IgA production by intestinal plasma cells is enhanced by selective gut-homing properties of

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