THEMES
Nutrient Tasting and Signaling Mechanisms in the Gut
V. Mechanisms of immunologic sensation of intestinal contents*

Fergus Shanahan

Department of Medicine, National University of Ireland, University College Cork and Cork University Hospital, Ireland


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Immune perception of intestinal contents reflects a functional dualism with systemic hyporesponsiveness to dietary antigens and resident microflora (oral tolerance) and active immune responses to mucosal pathogens. This facilitates optimal absorption of dietary nutrients while conserving immunologic resources for episodic pathogenic challenge. Discrimination between dangerous and harmless antigens within the enteric lumen requires continual sampling of the microenvironment by multiple potential pathways, innate and adaptive recognition mechanisms, bidirectional lymphoepithelial signaling, and rigorous control of effector responses. Errors in these processes disrupt mucosal homeostasis and are associated with food hypersensitivity and mucosal inflammation. Mechanisms of mucosal immune perception and handling of dietary proteins and other antigens have several practical and theoretical implications including vaccine design, therapy of systemic autoimmunity, and alteration of enteric flora with probiotics.

microflora; dietary antigens; oral tolerance; mucosal immunity; inflammatory bowel diseases; probiotics


    INTRODUCTION
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THE HUMAN IMMUNE SYSTEM REPRESENTS a complex of interacting mechanisms designed to interpret the environment, distinguish danger from harmless antigenic stimuli, and respond appropriately to maintain internal homeostasis. The immune system is equipped with receptors for detection of environmental antigenic change, an afferent or inductive limb, an efferent effector limb, central processing, and integration, and it has the capacity for memory, adaptation, and learning. Thus it possesses the necessary features to be regarded, justifiably, as a sensory organ---the sixth sense.

Interactions between host and environment occur primarily along mucosal surfaces. However, structural adaptation of the gastrointestinal mucosa to optimal absorption of dietary nutrients is a defense liability, vulnerable to breach by pathogens, because of its large surface area with only a single layer of enterocytes separating lumen from internal milieu. This threat is met by a highly specialized mucosal immune system with specific design constraints and requirements beyond those found within the systemic immune system. The critical design paradox for mucosal immunity is avoidance of unnecessary and potentially harmful reactivity to dietary proteins and enteric flora (oral tolerance), matched with a necessity for rapid responsiveness to episodic threats from pathogens. This requires continual antigen sampling of the environment, rigorous discrimination of danger signals from innocuous stimuli, and tight regulation of effector responses. Errors in these processes may be anticipated to lead to breakdown in mucosal homeostasis, the consequences of which include chronic inflammatory bowel disease and food hypersensitivity.


    OVERVIEW: IMMUNOLOGIC PERSPECTIVE OF INTESTINAL CONTENTS
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The antigenic contents of the intestine, from which the mucosal immune system must discriminate pathogenic and nonpathogenic constituents, are derived mainly from dietary sources and resident microflora. Collectively, this is a considerable antigenic load, with 1-2 kg of bacteria contained within the human gut and estimates of ingested food antigens over a lifetime expressed in tonnage. Despite digestive modification and intestinal barrier function, intact immunologically relevant proteins and other macromolecules normally penetrate the mucosa and acquire access to the immune system. There are three potential immunologic outcomes of mucosal exposure to dietary antigen; a local secretory IgA antibody response is likely to be induced, which is occasionally accompanied by a systemic immune response but more commonly is associated with a state of systemic immunologic hyporesponsiveness to the specific antigen challenge (oral tolerance). Thus immunity to dietary antigens may simultaneously involve positive (mucosal IgA induction) and negative (systemic hyporesponsiveness, oral tolerance) events. This implies a separate level of regulation and is a striking example of how the mucosal and systemic immune systems are operationally distinct.

Factors influencing immunologic outcomes of antigen exposure within the mucosa include the solubility or particulate nature of the antigen, its dose and frequency of administration, and a variety of genetic and other ill-defined host-related factors (8, 23, 24). Although outcomes vary with different experimental settings, particulate or replicating molecular complexes such as those associated with pathogenic organisms tend to be associated with local and systemic responses, whereas soluble nonreplicating antigens tend to induce tolerance. Experimental administration of high doses of antigen tends to lead to a profound state of clonal anergy or deletion of T cells, whereas multiple low doses are more likely to generate regulatory cells with a suppressive, albeit more variable, influence on individual responses (8). Oral tolerance represents an actively regulated state of specific nonresponsiveness that is maintained by multiple and probably non-mutually exclusive immunoregulatory mechanisms (8, 23, 24). As discussed below, the site of antigen sampling, and especially the nature of the local antigen-presenting cells, is a critical determinant for development of oral tolerance or immunity to intestinal antigens.

The resident microflora also present a highly varied profile of antigenic material to the mucosal immune system and, in addition, can influence the immunologic response to orally administered antigens (8, 23). Normal flora participate in an internet of lymphoepithelial and bacterial signaling, and the conditioning effect of signaling from the microflora on mucosal integrity is illustrated by the structural and functional alterations seen in a germ-free environment. These include reductions in epithelial turnover, motility, smooth muscle function, vascularity, and diminished anatomic and functional development of gut-associated lymphoid tissue (GALT) (2). Defective oral tolerance to ingested antigens has also been reported in germ-free animals, and bacterial lipopolysaccharide (LPS) enhances oral tolerance in some settings (8).


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The structural arrangement of GALT (organized or diffusely dispersed) reflects the functional compartmentalization of the mucosal immune response into sensory/inductive and effector limbs. The organized GALT consisting of isolated or aggregated lymphoid follicles (Peyer's patches) and mesenteric lymph nodes is the major inductive site for mucosal immune responses. A more diffusely arranged GALT is distributed throughout the lamina propria and epithelium, consisting of two distinct effector cell populations above and below the basement membrane; the intraepithelial lymphocytes (IEL) and the lamina propria mononuclear cells including lamina propria lymphocytes. These infiltrates represent the effector cell limb of mucosal immunity. Collectively, they account for the largest lymphoid mass in the body, tantamount to a state of "controlled" or physiological infiltration in ready alert at the environmental interface. Control, in this setting, is maintained by multidirectional heterocellular signaling within the mucosa and across the epithelial barrier (4, 14, 22).

After antigen sampling within the lymphoid follicles, if a positive response is induced, antigen-specific precursor T cells and IgA precursor B cells clonally expand and migrate through the mesenteric lymph nodes, where further maturation and multiplication occurs. They then home via the thoracic duct and circulation back to the lamina propria and epithelium (effector sites) and also populate distant mucosal tissues (see Fig. 1). Intermucosal traffic of effector cells implies that an immune response to enteric antigens may be reflected at a distant mucosal site such as the mammary gland. This accounts for the passive transfer of immunity to the same antigen by colostrum and milk to the breast-fed neonate. Current understanding of and controversies on the mechanisms and molecular determinants of intermucosal traffic and homing from inductive to effector sites have been reviewed recently and have important implications for vaccine design (3, 3a). However, it is noteworthy that although the anatomic distinction between inductive and effector sites within GALT is generally applicable, it is not absolute; as discussed below, immune responses may be induced within the intestinal epithelium under certain conditions.


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Fig. 1.   Representation of afferent (inductive) and efferent (effector) limbs of mucosal immune response to luminal antigens. M cells overlying lymphoid follicles within gut-associated lymphoid tissue (GALT) transport particulate antigens to dendritic and other antigen-presenting cells (macrophages). Dendritic cells process and present antigen in context of major histocompatibility complex (MHC) and in association with costimulatory molecules to T cells. Under normal circumstances, for innocuous antigens, usual outcome is the generation of interleukin (IL)-10 and transforming growth factor-beta (TGF-beta ), which drive the differentiation of T helper type 2 (Th2) and regulatory T cells (Th3 and Tr1), thereby promoting IgA responses and oral tolerance. In contrast, enterocytes may take up, process, and present soluble antigens by uncertain mechanisms in the context of MHC class II or CD1d molecules, and preferentially activate CD8 T cells. Other mechanisms of epithelial sampling and signaling may also be operational. IEL, intraepithelial lymphocyte.


    TEMPORAL ORGANIZATION: INNATE AND ADAPTIVE RESPONSES
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Mobilization of different immunologic effector cells in response to infection or foreign antigens occurs over varying time sequences. Innate or natural immunity, the first line of defense, is a rapid response to contain infection pending slower development of acquired or adaptive immunity, which is specific, more definitive, and exhibits memory. Innate immunity is an ancient, highly conserved defense system, phylogenetically older than adaptive immunity; its essential characteristic is its ability to distinguish species self from infectious non-self without elaborate antigen presentation mechanisms. Components of innate immunity include macrophages, natural killer cells, defensins, and the complement cascade, all of which are represented within the intestinal mucosa.

The essential difference between the innate and adaptive responses is the mechanism by which they recognize microorganisms and other antigens. Cells of the adaptive immune response, alpha beta -T and B lymphocytes, recognize and recall foreign material using antigen-specific receptors (T-cell receptor and immunoglobulins), whereas the innate immune response identifies microorganisms by pattern-recognition molecules or receptors (11). The molecular patterns are frequently surface carbohydrate structures or nucleic acids. They are common to groups of pathogens and include LPS of Gram-negative bacteria, glycolipids of mycobacteria, mannans of yeast, and double-stranded RNAs of viruses. With the identification of a group of proteins referred to as toll-like receptors (TLRs) on human macrophages, the molecular signaling events for responses to bacterial LPS have been identified. Intracellular signaling events by TLR trigger activation of the transcription factor NF-kappa B, which leads to expression of multiple immunomodulatory genes including cytokines and costimulatory molecules required for antigen presentation and generation of adaptive immunity by T and B cells (11). Thus the innate immune response not only provides early defense but also initiates the adaptive immune response.

Several lines of evidence have indicated a central role for intestinal intraepithelial gamma delta -T cells (IELs) in coordinating the interplay between innate and adaptive mucosal immunity. gamma delta -T cells may be regarded as components of both innate and adaptive immunity. They differ from the other T-cell lineage (alpha beta -T cells) in their mode of antigen recognition. They do not require antigen processing; protein antigens are recognized directly, and they can also respond to different ligands, including small phosphate-containing nonpeptides (6). A subset of human IEL gamma delta -T cells have been shown to be stimulated by a previously unrecognized class of antigens, the alkylamines (5). These alkylamines are chemically and biologically distinct from protein, lipid, or phosphate antigens. They are produced by bacteria, including bowel flora and pathogens, and are present in certain foods, including edible plants and tea. Human IEL gamma delta -T cells have also been shown to directly recognize major histocompatibility complex (MHC) class I-related molecules MICA and MICB, which are induced in epithelial cells by stress that might result from infection or injury (9). By recognizing self-associated molecules induced on injured or infected epithelial cells, they seem well positioned and suited to epithelial surveillance from a variety of insults. Once activated by injured epithelium, they produce epithelium-specific growth factors, chemokines, and other cytokines that promote healing, initiate an adaptive immune response, and recruit inflammatory cells.


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Uptake of antigens occurs primarily by specialized epithelial M cells overlying lymphoid follicles. The properties of the apical membranes of the M cell favor selective adherence of pathogenic and nonpathogenic microorganisms and particulate antigens. After transcytosis they are delivered to the underlying lymphoid cells, which are invaginated in the abluminal aspect of the M-cell membrane. This intimate lymphoepithelial juxtaposition not only favors antigen transport but also reflects the direct influence of mucosal lymphoid cells on epithelial plasticity and differentiation toward the M-cell phenotype (15). As with any sampling system, M-cell transport is vulnerable to subversion by invasive bacterial pathogens and some viruses (19). Much of the ultrastructural detail and some of the molecular mechanisms involved in such processes have been elucidated, and they continue to attract considerable research attention because of their importance to current strategies for vaccine design.

Under normal circumstances, material transported by M cells is taken up by antigen-presenting cells. These include B cells and macrophages (3, 3a), but recent attention has focused on dendritic cells, which have a central role in antigen presentation to T cells and initiation of immune responses (1). Dendritic cell heterogeneity has been described by several investigators, and the apparent tissue-specific specialization of dendritic cells within mucosal lymphoid follicles may be a critical determinant of immune response to different antigens (13). A defining characteristic of mucosal immune responses to enteric antigens is the predominant induction of T helper cells associated with type 2 and/or type 3 cytokine profiles (Th2 and Th3 cells) (see Fig. 1). Cytokine production by Th2 cells includes interleukin (IL)-4, IL-5, and IL-10, which drive the production of IgA, whereas Th3 cells produce transforming growth factor-beta , which induces B cells to switch to the IgA isotype and is critical for the induction of "low-dose" oral tolerance (8, 24). Thus generation of Th2 and/or Th3 cells is regarded as the default mucosal response pathway for innocuous luminal antigens, and dendritic cells from murine Peyer's patch but not spleen dendritic cells have been shown to preferentially produce IL-10 and induce differentiation of T cells along a Th2 pathway (13). Expansion of dendritic cells in vivo has also been shown to enhance the induction of oral tolerance (25). Additional factors including local cytokine milieu and stage of lymphocyte cell cycle (21) may influence the choice of differentiation pathway for mucosal T cells under different circumstances.

Mucosal exposure to antigenic material from pathogenic organisms such as Salmonella typhimurium is thought to trigger an alternative pathway of dendritic cell maturation and macrophage activation with production of IL-12, which induces a Th1 cytokine response, associated with interferon-gamma , IL-1, and tumor necrosis factor-alpha production (13). Elaboration of interferon-gamma further enhances IL-12 production and expression of IL-12 receptors. This cytokine response may be common to a variety of intracellular microbial organisms because the associated macrophage activation is required for optimal host defense. The danger signals driving this pathway of dendritic cell maturation are not well clarified and may involve host-derived cytokines and bacterial stimuli such as LPS, lipoteichoic acid, bacterial DNA, and viral and double-stranded RNA (1). The mucosal Th2/Th3 default pathway may also be overridden in certain chronic inflammatory disorders such as Crohn's disease, in which mucosal injury appears to be the result of prolonged and inappropriate induction of Th1 cytokines (24).


    SAMPLING AND SIGNALING BY ENTEROCYTES
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The intestinal epithelium is a central component of the mucosal immune response to intestinal antigens, participating in both afferent and efferent limbs. The epithelial role in the efferent limb of humoral immune responses has long been recognized in the form of enterocyte transport of secretory IgA, and enterocytes have since been shown to provide regulatory cytokine signals for other efferent immune and inflammatory events (22). Several lines of evidence suggest that enterocytes may also function as afferent sensors of danger within the luminal microenvironment. By antigen sampling, presentation, and signaling, it seems that enterocytes may discriminate between pathogens and commensals. The epithelium can elaborate chemokines and other proinflammatory mediators, thereby alerting the host to a breach in the mucosal barrier and focusing innate and acquired immune responses to the site of infection. This is accomplished through bidirectional communication with adjacent and subjacent lymphocytes (14, 22).

In addition to the M-cell antigen sampling pathway, there are several potential alternative routes by which antigens may be handled within the epithelium. Although particulate antigens and certain microbes are preferentially sampled by M cells, soluble antigens are taken up by surface enterocytes into endosomes by fluid-phase pinocytosis. After trancytosis and partial proteolysis, antigen fragments may be expressed on the surface of the enterocyte in association with MHC class II molecules, which are constitutively expressed by enterocytes. The remarkable feature of this form of antigen presentation is that local immunosuppressive effects are generated by either preferential activation of CD8 T cells (18) or elaboration of prostaglandin E2 or other soluble suppressors. Unlike professional antigen-presenting cells, enterocytes do not constitutively express costimulatory molecules required for T-cell responses to antigen. Therefore, interactions between antigen-presenting enterocytes and CD4 T cells are likely to result in anergy rather than activation. This is compatible with oral tolerance under normal circumstances and appears to be defective in patients with inflammatory bowel diseases (18). Mechanistic details of the process vary depending on the cell lines studied, and its kinetics may be influenced by cytokines and the immune status or sensitization of the host (18). However, it is doubtful that epithelial MHC II-related antigen presentation is important in vivo outside the setting of inflammation. Thus MHC class II molecules are expressed on the luminal rather than basolateral aspect of the enterocyte, which suggests that they are not involved in lymphoepithelial interactions under normal circumstances. It is possible that luminally expressed MHC class II molecules serve as sensory receptors for partially processed (digested) peptides within the lumen. In addition, cytokine-mediated (particularly interferon-gamma mediated) upregulation of expression may call this antigen-presenting pathway into play on the abluminal enterocyte membrane in inflammatory disorders.

Another perhaps more dominant pathway for antigen presentation by enterocytes is MHC independent and involves the CD1 system. The CD1 family of antigen-presenting molecules are expressed on professional antigen-presenting cells of the immune system (dendritic cells, B cells, and macrophages) and also on human gastrointestinal epithelial cells (CD1d). Presentation of antigens by CD1 molecules requires antigen uptake and processing, CD1 being a restriction element rather than an accessory molecule. It is responsible for T-cell recognition of lipids and glycolipids found in cell walls and membranes of mycobacteria and mammalian cells (20). This suggests that epithelial cells may present nonprotein antigens from enteric microorganisms in the context of CD1d molecules to intraepithelial T cells, which then elaborate molecules that initiate or regulate the immune response.

Receptors for the Fc component of IgG have also been demonstrated on the apical surface of enterocytes (12). Whether these are involved in sampling and uptake of antigen complexed with IgG from the lumen is uncertain. Finally, dendritic cells have recently been observed within the intestinal epithelium in rats and may be another immunosensory and immunoregulatory signaling mechanism for the epithelial compartment (17). Intraepithelial dendritic cells remain to be demonstrated in other species.

It is well established that epithelial cells produce a range of chemokines, cytokines, and other soluble mediators in response to infection with invasive and noninvasive organisms (4, 14). In effect, the epithelium transduces danger signals from the lumen to the underlying GALT. On exposure to pathogenic infection, epithelial cells launch the innate mucosal immune response with differential and regulated expression of chemokines leading to mucosal infiltration with neutrophils and subsequently with cells of the acquired immune response. The composition of the inflammatory infiltrate is dependent, in part, on the type and kinetics of chemokine production by the epithelium, and this varies with the nature and degree of invasiveness of the pathogen (14).

Some pathogenic bacteria have evolved ingenious mechanisms to exploit both epithelial and mucosal immune responses. Enteropathogenic Escherichia coli adhere to intestinal epithelium using an outer membrane protein, intimin, the ligand for which is inserted into the host enterocyte by the bacterium (translocated intimin receptor). Because intimin is a bifunctional molecule binding also to beta 1-integrins on T cells, it can costimulate antigen-primed mucosal T cells in a synergistic manner and initiate a mucosal Th1 response associated with mucosal thickening, crypt cell hyperplasia, and shedding (10). The result of this bacteria-induced upregulation of the mucosal immune response is increased surface area and epithelial renewal, thereby facilitating fresh colonization and promoting transmission caused by increased fecal shedding.


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Immunologic perception and discriminatory responses to intestinal contents represent remarkable conservation of defense resources and adaptation to the local environment. The mechanisms involved in antigen handling and intermucosal traffic have implications for vaccine design, whereas oral tolerance has therapeutic applications in the suppression of systemic autoimmune and mucosal hypersensitivity disorders (8, 24). Research advances in mucosal immunity are already being translated to a new generation of functional foods. These are designed to exploit oral tolerance by various strategies including mucosal adjuvants and transgenic plants expressing autoantigens (16). It is also noteworthy that epithelial and mucosal immune signaling is not exclusive to pathogenic organisms; normal resident flora also exchange signals with the epithelium and mucosal immune response (4). In this context, the use of probiotic organisms to favorably alter the indigenous flora and generate beneficial mucosal immunomodulatory effects may have a more sound therapeutic rationale than previously considered (7).


    ACKNOWLEDGEMENTS

The author is supported, in part, by the Health Research Board of Ireland.


    FOOTNOTES

* Fifth in a series of invited articles on Nutrient Tasting and Signaling Mechanisms in the Gut.

Address for reprint requests and other correspondence: F. Shanahan, Dept. of Medicine, Cork Univ. Hospital, Cork, Ireland (E-mail: Fshanahan{at}ucc.ie).

Received 28 October 1999; accepted in final form 28 October 1999.


    REFERENCES
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Am J Physiol Gastroint Liver Physiol 278(2):G191-G196
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