Gastroenterology
Volume 127, Issue 1 , Pages 300-309, July 2004

Gastrointestinal dendritic cells play a role in immunity, tolerance, and disease

  • Janine Bilsborough

      Affiliations

    • Department of Autoimmunity and Vascular Biology, Amgen, Seattle, Washington, USA
    • Dr. Bilsborough’s current address is: Zymogenetics, 1201 Eastlake Avenue E, Seattle, Washington 98102.
    • ,
  • Joanne L. Viney

      Affiliations

    • Corresponding Author InformationAddress requests for reprints to: Joanne L. Viney, M.D., Amgen, 51 University Street, Seattle, Washington 98101, USA, fax: (206) 217-0494
    • Department of Autoimmunity and Vascular Biology, Amgen, Seattle, Washington, USA

Received 21 November 2003; accepted 22 January 2004.

Article Outline

Abstract 

Discrimination between beneficial commensal organisms and potentially harmful pathogens is a central component of the essential role that gut immune cells play in maintaining the balance between immune activation and tolerance. Antigen presenting cells (APC) are the key to this process, and the type of APC, including epithelial cells, B cells, macrophages, and dendritic cells (DC), in the gut is varied. The purpose of this review is to focus on the vast amount of data that has recently been generated on gastrointestinal dendritic cells in the context of their potential function and contribution to mucosal immunity, tolerance, and disease.

Abbreviations:  APC, antigen presenting cells, DC, dendritic cells, MLN, mesenteric lymph nodes, PLN, peripheral lymph nodes

 

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DC populations and their location in the gastrointestinal tract 

In an attempt to generate a comprehensive review of the current literature relevant to the function of the immune system in the gastrointestinal tract, we focus on studies that have involved DC isolated from the gut, as opposed to those studies of DC from other tissue origins (i.e., spleen and peripheral lymph nodes [PLN]), because it is increasingly evident that the tissue microenvironment, among other factors, can significantly influence DC responses to stimulation.

The phenotypic analysis of DC within tissues of the gastrointestinal (GI) tract has identified a plethora of different subtypes. Studies on the Peyer’s patch, arguably the most studied lymphoid tissue in the gastrointestinal tract, suggest the presence of at least 4 different subsets of CD11c+ dendritic cells based on the expression of CD11b and CD8α+ surface markers: CD11b+CD8α−, CD11b-CD8α+, CD11b-CD8α−, and CD11cintCD8α+B220+.1, 2 Studies of DC populations in the mesenteric lymph nodes (MLN) have been complicated by the use of different surface markers and varied animal model systems, but data suggest that 2 additional populations are present, including CD11b+CD4+ DC (DC with authentic CD4 expression represent a minor population of less than 5%) and a dermal-derived DC population (CD4-CD8-DEC-205int) suggested as the equivalent of interstitial-derived DC.3, 4 Functional differences have been demonstrated for these different DC populations, and these will be highlighted throughout our review.

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Antigen uptake by DC in the GI tract 

The organization of the mucosal immune system has been elegantly reviewed elsewhere5 and can be roughly divided into organized lymphoid tissues (including Peyer’s patches and MLN) and generalized or diffuse tissues interspersed with effector cells of the immune system (lamina propria and intestinal epithelium). Traditionally, Peyer’s patches have been studied as the main site for induction of mucosal immunity, given their intimate localization with the intestinal lumen, the presence of B-cell and T-cell follicles, and specialized M cells, which pass particulate antigens from the lumen to awaiting antigen-presenting cells located beneath the epithelium.6 However, although somewhat controversial, there is now substantial evidence to suggest that Peyer’s patch (and M cells by association) may not be absolutely required for induction of either immunity or oral tolerance.5 This does not appear to apply to the MLN however.7, 8

Soluble antigen uptake by DC and oral tolerance 

Oral tolerance is required for the maintenance of intestinal homeostasis and arises following exposure of the intestinal immune system to soluble antigens. Kinetic analysis of antigen-specific T-cell expansion using TCR transgenic T cells following oral antigen delivery has been used in an effort to clarify in which tissues the early cellular events might occur following delivery of oral antigens, and these studies highlighted DC as playing an important role in the process of tolerance induction. Although the results of various studies have varied in terms of where T-cell activation occurs preferentially (either locally or in the periphery), all studies have shown that induction of oral tolerance is an active process, resulting in the expansion of antigen-specific T cells early after feeding antigen9, 10, 11, 12, 13 and that DC are likely to be involved in the process. The very early work demonstrated that the expansion of DC in vivo enhanced oral tolerance induction and enhanced antigen-induced expansion of T cells in gut-associated lymphoid tissue (GALT) after feeding,13 implicating DC as being integral to the process. However, it wasn’t until recently, through visualization of antigen uptake by APC in the Peyer’s patch and MLN, that the precise contribution of GALT DC to antigen presentation in the intestinal tract became more obvious. Highly sensitive flow cytometric detection of peptide antigen presentation (through the use of magneto fluorescent liposomes) has suggested that, although APC in the Peyer’s patch preferentially present orally administered peptide antigen compared with APC in the MLN, naı̈ve T-cell activation and division occur predominantly in the MLN.14 These authors went on to demonstrate that the frequency of peptide-presenting cells was similar in Peyer’s patch-deficient mice and that Peyer’s patches did not significantly contribute to T-cell activation, lending further support to suggestions that Peyer’s patches may not be absolutely required for T-cell responsiveness in the gut.

Other studies monitoring T-cell expansion in the MLN following tolerogenic and immunogenic, adjuvant-assisted, administration of oral antigen have demonstrated that the level of T-cell activation appears similar in both cases, although T cells in the MLN of orally tolerant mice proliferate less compared with T cells in the MLN from orally primed mice.11 Assessment of T-cell proliferation in the peripheral lymph nodes showed no change under conditions of priming or tolerance, suggesting that the controlling mechanism underlying tolerogenic or immunogenic immune responses lies largely within the lymph nodes of the gut. In an attempt to define the DC subsets that might contribute to the presentation of oral antigen under these conditions, expression of fluorescently labeled antigen has been followed and the DC subsets involved in antigen uptake phenotyped. In these studies, when soluble antigen was fed to induce oral tolerance, antigen was found on both CD8α− and CD8α+ DC in PLN, but only on CD8α− DC in the MLN. Under immunogenic conditions, antigen was only found on CD8α− DC in PLN.10 These data suggest that the same population of DC can present antigen under immunogenic and tolerogenic conditions; however, the localization of these DC and their direct environment may be critical for driving the decision process between tolerance and immunity. Isolation of these DC populations under the above mentioned test conditions and assessment of their subsequent function in vitro may shed some light on factors contributing to the result of tolerance or immunity. As discussed later, the signaling event that determines the outcome of active immunity vs. tolerance is not known, but the general assumption is that soluble antigens are poor immunogens and induce tolerance because they fail to up-regulate costimulatory molecules on APC. However, in the studies described above, the authors found no differences in CD80 or CD86 levels on DC expressing antigen when antigen was given in either the tolerogenic or immunogenic forms.

Particulate antigen uptake by DC 

The main route for particulate antigen to gain access to the mucosal immune system is thought to be through M cells. In the Peyer’s patch, DC are in close contact with M cells and have been shown to colocalize with Salmonella typhimurium a few hours after bacterial infection, implicating DC as a major source of bacterial uptake in this tissue.15 Elegant studies of DC ingesting fluorescent polystyrene microparticles have demonstrated that the majority of CD11c+ DC ingesting the particles could be located in the subepithelial dome (SED) just under the follicle-associated epithelium (FAE). Phenotypic analysis determined that the majority of DC were negative for both CD11b (although some were CD11b intermediate) and CD8α.16 Interestingly, macrophages present in the sections alongside inert macroparticles were shown not to be involved in their uptake.

Bacteria transported through Peyer’s patch M cells are not the only source used by intestinal DC for gaining access to microbial flora antigens from the gut lumen. DC have been described in the lamina propria, where they are distributed along the entire intestinal epithelium.17 From here, they have been shown to sample bacteria from the gut lumen by extending dendrites through epithelial cells of the gut barrier, conserving barrier integrity by the expression and modulation of tight junction proteins, including junctional adhesion molecule (JAM), occludin, claudin 1, and zonula occludens 1.18 It is not clear whether this mechanism is constitutively active or induced in response to signals from epithelial cells that have been in contact with bacteria in the lumen. Contact between epithelial cells and bacteria products such as flagellin can result in up-regulation of proinflammatory cytokine and chemokine genes.19, 20, 21 Although both pathogenic and nonpathogenic bacteria can express flagellin, it has been demonstrated that only invasive pathogens efficiently transcytose.19

The ability of DC to sample the luminal contents may be an important factor in surveillance of pathogens in the gut environment. If so, the ability to distinguish between pathogens and commensals is necessary for the maintenance of intestinal homeostasis. One proposed mechanism is that DC utilize their innate receptor repertoire of toll-like receptors (TLR) and C-type lectins to discriminate between microbial-associated molecular patterns (MAMP) expressed by commensal bacterial and pathogen-associated molecular patterns (PAMP).22, 23 TLR are transmembrane proteins that can interact with certain microbial patterns to direct the subsequent immune response (reviewed in Takeda et al.24) (Table 1). C-type lectins on the other hand (Table 2) preferentially bind to carbohydrate antigens and are associated with antigen uptake, including virus, bacteria, parasites, and yeasts.25, 26, 27, 28, 29, 30 C-type lectins may also be important in the migration of DC.31

Table 1. Toll-Like Receptors and Their Ligands
TLR familyLigandsOrigin
TLR1Tri acyl lipopeptidesBacteria, mycobacteria
Soluble factorsNeisseria meningitides
TLR2Lipoprotein/lipopeptidesPathogens
PeptidoglycanGram-positive bacteria
Lipoteichoic acidGram-positive bacteria
LipoarabinomannanMycobacteria
A phenol-soluble modulinStaph. epidermidis
GlycoinositolphospholidsTrypanosoma cruzi
GlycolipidsTreponema maltophilum
PorinsNeisseria
ZymosanFunge
Atypical LPSLeptospira interrogans
Atypical LPSPorphyromonas gingivalis
HSP70Host
TLR3Double-stranded RNAVirus
TLR4LPSGram-negative bacteria
TaxolPlant
Fusion proteinRSV
Envelope proteinsMMTV
HSP60Chlamydia pneumoniae
HSP60Host
HSP70Host
Type III repeat extra domain A of fibronectinHost
Oligosaccharides of hyaluronic acidHost
Polysaccharide fragments of heparin sulfateHost
FibrinogenHost
TLR5FlagellinBacteria
TLR6Diacyl lipopeptidesMycoplasma
TLR7ImidazoquinolineSynthetic compound
LoxoribineSynthetic compound
BropirimineSynthetic compound
TLR8 ?
TLR9Cpg DNABacteria
TLR10 ?

NOTE. Adapted from Takeda et al.34

Table 2. C-type Lectins
C-type lectinTypeCell typeLigandFunction
MMR (CD206)IDC, LC Mono, Mac, DMECMannose, fucose, sLeXAntigen uptake
DEC 205 (CD205IDC, LC, thymic EC?Antigen uptake
Dectin 1IIDC, LCB-glucanT-cell interaction
Dectin 2IIDC LC?Antigen uptake
Langerin (CD207)IILC?
DC-SIGN (CD209)IIDCgp120 (HIV), SIV, mannan, ICAM-2, ICAM-3Migration, antigen uptake, T-cell interaction
BDDCA-2IIPlasmacytoid DC?? Antigen uptake
DLECIIDC, Mono, Mac, PMN, B??
CLEC-1IIDC??

NOTE. Adapted from Figdor et al.31

Under steady-state conditions, lamina propria DC are also known to transport apoptotic epithelial cells to T-cell areas of the MLN.32, 33, 34 This circulation of DC from the lamina propria has been suggested as one mechanism by which DC can maintain tolerance to normal gut antigens.32, 35, 36, 37, 38 In the rat, these circulating DC could be divided into 2 populations based on their expression of CD4. CD4+OX41+ DC expressed MHC class II and CD11b/c and appeared to be more effective stimulators compared with the CD4−OX41− DC population but were found to be excluded from the T-cell areas of the MLN, whereas CD4− DC carry apoptotic enterocytes to the T-cell areas of MLN.4, 32 This constitutive migration of DC from the intestinal mucosa and other peripheral tissues into lymphatic vessels can be accelerated by systemic injection of inflammatory cytokines or microbial products.39, 40, 41 The mechanism behind this increase in DC movement following stimulation is believed to be coordinated through differential regulation of chemokines and chemokine receptors.

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Migration of DC in the GI tract 

DC migration is an important attribute for the ability of DC to control and disseminate an immune response, and a number of key studies have highlighted the diversity in chemokine responsiveness by different DC populations located in the same intestinal tissues. Because DC migration is thought to be largely under the control of chemokines and chemokine receptors, it is informative to determine chemokine receptor expression and reactivity to chemokines by different GI DC populations in vitro and in vivo. Table 3 summarizes data on chemokine receptor expression by a number of different DC populations from the mouse Peyer’s patch. In general terms, MIP-3α appears fundamental in guiding immature DC expressing CCR6 from blood to intestinal tissues. MIP-3α is highly expressed in gut epithelium42 and in the FAE overlying the dome regions of the Peyer’s patch.43, 44

Table 3. Chemokine Receptor Expression on Mouse PP DC Subsets
Chemokine receptorPP DC subset
CD8α+CD8α−CD11b−CD11b+
CCR1++++++
CCR2++++
CCR5−+−
CCR6−++
CCR7+++++
CCR9+++
CCR10−+++

NOTE. Adapted from Zhao et al.46

CD11b+ DC in the Peyer’s patch are located at the SED, and these DC migrate toward MIP-3α (CCL20) in vitro. In addition, CCR6-deficient mice were originally reported to have fewer CD11b+ DC in the dome regions of the Peyer’s patch.43, 45 Thus, it is hypothesized that MIP-3α is a major chemokine controlling localization of DC in the Peyer’s patch44 and in the lamina propria.21 However, a recent study, reportedly using more sensitive immunofluorescence techniques, showed that CD11b+ DC could still be found in the SED regions of CCR6-deficient animals.46 The authors went on to demonstrate that CD11b+ DC present in the Peyer’s patch of CCR6-deficient mice may be attracted through the chemotactic activity of CCL9 (MIP-1γ, MRP-2, or CCF18). The receptor for CCL9, CCR1, is highly expressed on CD11b+ DC, and these DC display some migration activity toward CCL9 in vitro.46 Blocking CCL9 activity in vivo diminished the presence of CD11b+ DC in the SED of the Peyer’s patch; however, CCR1-deficient mice revealed no significant decrease in CD11b+ DC in the dome region of the Peyer’s patch. This finding leaves questions as to the existence of independent activity of CCR1 or the possible existence for another receptor for CCL9. It is unclear whether all CD11b+ DC express both receptors necessary to migrate to the SED, i.e., CCR6 and the receptor for CCL9, or if there is another subset of CD11b+ DC with differential expression of the receptors for either chemokine.46 In contrast to CD11b+ DC, CD8α+ DC express CCR7 and migrate toward ELC (CCL19), which is expressed in the T-cell-rich regions of the Peyer’s patch.44 The CD8− CD11b− double-negative population of DC can be found in both the dome region, where they constitute the majority of DC, and the interfollicular region of the Peyer’s patch.2, 44

As mentioned previously, the majority of CD11c+ DC ingesting fluoresbrite polystyrene microparticles are located in the SED and are negative or intermediate for CD11b and negative for CD8α. Of note, these DC did not migrate to the interfollicular regions following particle uptake but remained in the SED for a prolonged period of time. Only when mice were fed cholera toxin, or live attenuated Salmonella, did microparticle loaded DC migrate to the T-cell zones and B-cell follicles, suggesting that stimulation is required for mobility.16 Interestingly, it was the CD11b+ DC in the Peyer’s patch that have been implicated in the presentation of Toxoplasma gondii soluble trophozoite antigen to T cells.44 Why these 2 studies should highlight different DC subsets in this process is unknown but may be due to differential responsiveness of DC subsets to different types of microbial stimuli. In the rat, it is the OX-62 positive DC that were found to emigrate from the Peyer’s patch to MLN following ingestion of bacteria.47

Migration of DC from the SED of the Peyer’s patch involves loss of their responsiveness to MIP-3α and up-regulation of CCR7, which permits responsiveness to MIP-3β (ELC) and 6Ckine (SLC), inducing migration to high endothelial venules in lymphatic vessels and consequently to T-cell-rich regions of draining lymph nodes. On encounter with T cells, mature DC can receive additional maturation signals from likely candidates of the TNFR family such as CD40L, RANKL, 4-1BBL, and OX40L to enhance T-cell triggering and initiate the immune response, whether that be active immunity or tolerance.48

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GI DC contribution to immunity 

Engagement of the members of the TNFR family on DC is a well-published methodology to enhance DC immunostimulatory function. However, DC isolated from GI tissues can exhibit different responses to such stimuli. Engagement of RANK on DC by RANKL that is usually expressed on activated T cells has been shown to stimulate the secretion of cytokines such as IL-1, IL-6, and IL-12 by splenic DCs but appears to induce IL-10 transcription in Peyer’s patch DC.49 It is tempting to speculate, therefore, that gut-associated DC are more prone to induce tolerogenic immune responses; however, studies have shown that there are different DC populations within gut-associated tissues that respond differently to the same stimuli.1, 2 Thus, the outcome of stimulation might depend on the local interaction between DC populations and their interaction with T cells. Indeed, the outcome for antigen exposure in the gut should be appropriate to the threat imposed by the source of antigen, which implies a level of plasticity in the immune response. Certainly, proinflammatory cytokines such as IL-1α can modulate DC to result in active immunity as opposed to tolerance.50

Clearly, local immune responsiveness to bacteria occurs under steady-state conditions in a normally colonized gut, and such immune interaction contributes to the development of the localized mucosa-associated immune system.51 The mechanisms by which DC are able to keep translocated bacteria at bay (after the bacteria have translocated across the epithelial barrier) are not completely understood, but a recent study52 suggests that IL-23 may play a key regulatory component. IL-23 is comprised of 2 subunits, 1 of which is shared with IL-12 (IL-23 comprises IL-23p19 and IL-12p40, whereas IL-12 comprises IL-12p35 and IL-12p40). Studies using animals that express firefly luciferase under the influence of the IL-12p40 promoter demonstrated constitutive expression of IL-12p40 promoter activity in the small intestine accompanied by IL-23p19 but not IL-12p35 mRNA. Additional IL-23 protein complex appears to be produced in response to bacterial flora, and it is the CD11c+ CD8− CD11b− “double-negative” DC located in the lamina propria that appear to be the major source for the IL-12p40 activity.52 Colonic DC have also been demonstrated to induce differential cytokine production following stimulation with bacteria, and it appears that the type of cytokine produced might be dependent on the nature of the microbial stimulus.53

The balance between immunity and tolerance is essential for a healthy gut. Dysregulated immune responses to bacterial flora are believed to result in chronic intestinal inflammation, a disorder known as inflammatory bowel disease (IBD) in humans, and it is therefore necessary to ensure that immune responsiveness to intestinal microflora remains under tight regulation. Whether this regulation is achieved through activation of DC by key bacterial components that elicit differential cytokine production such as IL-10 vs. IL-12 or IL-2353 or whether regulation occurs through distinct DC populations that exhibit either immunogenic or tolerogenic responses is unclear at present.

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GI DC contribution to tolerance 

Potential mechanisms underlying tolerance in the GI tract have been thoroughly reviewed elsewhere.54 In this section of the review, we will highlight some of the major points, with particular focus on the role of DC in tolerance under steady-state conditions and tolerance induced following oral administration of protein. The potential mechanisms for oral tolerance induction have included functional T-cell anergy/deletion or induction of regulatory T cells that produce TGF-β (Th3) or IL-10 (Tr1). Although conventional CD4+CD25+ T regulatory cells generated in the thymus55 are thought to play a central role in inhibiting the development of intestinal inflammation and IBD,56 studies on mucosally induced tolerance57, 58, 59 suggest that naı̈ve CD4+ T cells in peripheral tissues can be differentiated and taught to exhibit regulatory function (i.e., Tr1 and Th3 cells).

The role of DC in the induction of oral tolerance has been alluded to through studies showing enhanced oral tolerance following expansion of DC in vivo.13, 60 DC may achieve this through a number of different mechanisms Figure 1, including level of maturation at the time of antigen presentation,61, 62 signaling through novel receptor ligand interactions,63 and control of T-cell proliferation through the secretion of immunosuppressive cytokines, including IL-10, TGF-β, or IFN-α64, 65, 66, and metabolites such as indoleamine 2,3 dioxygenase IDO.67 Although there is substantial evidence that DC, both in the periphery and from local mucosal tissues, can induce T cells that exhibit regulatory function, it is becoming clear, as we have seen already, that DC subsets from different tissues may exhibit different functions to similar stimuli. We have recently demonstrated that a mucosally derived population of plasmacytoid DC in the mouse induces de novo differentiation of Tr1-like cells that secrete IL-4 and IL-10, even following maturation of the DC with CpG.1 Recent studies of mouse plasmacytoid DC from the bone marrow and spleen, however, show that this DC subset can induce a Th1 T-cell phenotype when stimulated by CpG,68 suggesting that the same DC population derived from different tissues respond differently to the same stimuli. Differences in tissue-specific DC function have also been highlighted by recent publications demonstrating that gut-derived DC also induce T-cell gut tropism,69, 70 suggesting very specific effects resulting from the outcome of T-cell contact with DC isolated from different tissues.

  • View full-size image.
  • Figure 1. 

    Numerous mechanisms have been reported for DC suppression of T-cell immune responses. (A) Thymus-derived regulatory T cells (CD4+CD25+ Treg cells) can induce the production of indoleamine 2,3 dioxygenase (IDO) through CTLA-4-B7 via the induction of IFN-γ (a). IDO is an enzyme that exhibits immunomodulatory activity on T cells by catabolism of tryptophan (Trp), an essential amino acid for cellular proliferation. IDO is under the regulation of IFN-γ and can be induced by the presence of IFN-α, either from the DC themselves or from other sources (b). Prostaglandin E2 (PGE2) has been shown to down-regulate DC immunostimulatory function through increased production of IL-10. PGE2 production by DC also down-regulates leukotriene B4 (LTB4), IL-12, and MHC Class II, thus resulting in down-regulation of immune responses. (B) Serrate1, a ligand for Notch1, can differentiate peripheral naı̈ve CD4+ T cells into regulatory cells. Suppression of cellular proliferation through transfer of Serrate1-induced regulatory T cells is antigen specific and induces down-regulation of IL-2 and IFN-γ in responding T cells. (C) IL-10, TGF-β, and IFN-α have all been implicated in the induction of T cells with regulatory properties. Regulatory T cells that mediate suppression of proliferative T cell responses, other than thymically derived CD4+CD25+ T regulatory cells, have been named Tr1 and Th3, based on their cytokine profiles. Tr1 cells produce IL-10 with little to no IL-4, whereas Th3 cells are defined as primarily TGF-β producers along with various amounts of IL-4 and IL-10. (D) The repetitive stimulation of naı̈ve CD4+ T cells with allogeneic immature DC can result in the generation of T cells with suppressive properties. These T cells proliferate poorly and induce high levels of IL-10; however, their inhibitor activity was found to be strictly cell-contact dependent. These immunosuppressive mechanisms of DC may not necessarily be mutually exclusive.

Even within the same mucosal tissues, there are different DC populations that exhibit a different array of functions under the same stimulation conditions. CD11c+ CD11b+ DC in Peyer’s patch, but not in the periphery, have a particular capacity to produce IL-10, whereas CD11c+ CD8α+ DC and CD11c+ CD11b− CD8α− “double negative” DC produced IL-12p70 following stimulation with CD40L. Furthermore, the CD11c+ DC from the Peyer’s patch can stimulate rapid antigen-specific T-cell proliferation and induction of IL-4 and IL-10 from stimulated T cells.2 These data support a role for the Peyer’s patch tissue microenvironment in modulating these functional phenotypes, and some have published evidence suggesting that the Peyer’s patch microenvironment, in general, may be immunosuppressive.71 Perhaps unrelated to this, but nevertheless interesting to note, colitis in mice deficient of Peyer’s patches and MLN is associated with increased disease severity.72 Thus, although Peyer’s patches may not be required to initiate immunogenic or tolerogenic immune responses, the presence of these organized lymphoid tissues may contribute to sustained immunosuppression.

Most studies have attributed the ability of DC to suppress T-cell immunity either to the production/induction of immunosuppressive cytokines or the decreased expression of costimulatory molecules (reviewed in Steinman et al.22). As previously mentioned, the general assumption for tolerance induction by soluble antigens is that soluble antigens fail to up-regulate costimulatory molecules on APC. However, studies using the engagement of CD40 through a stimulatory antibody were found to up-regulate CD86 expression on DC but did not inhibit oral tolerance induction of CD4+ T cells.73 Similarly, when levels of costimulatory molecules have been studied on mucosally derived DC following administration of antigen either in an immunogenic or tolerogenic form, no differences were observed.10 Thus, the signaling events that determine the outcome of active immunity vs. tolerance may be complicated. Clarification of these events will be important in determining suitable targets for treatment of disease.

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GI DC contribution to disease 

Animal model systems of colitis have been used extensively in an effort to determine the possible mechanisms that contribute to the initiation of colitis in humans.74 One model in particular has been very well characterized and involves the transfer of CD45RB high CD4+ T cells to SCID mice, which leads to the development of chronic colitis with intestinal pathology similar to that seen for IBD in humans.75 Studies focusing on the early events of this model implicated a role for DC in the manifestation of disease because transplanted T cells were shown to form aggregates with CD11c+ DC in the lamina propria, in which they subsequently underwent cellular proliferation.76 There was an observed 2- to 4-day delay between the first detectable influx of T cells in the MLN and the clustering of T cells: DC aggregates in lamina propria, and the authors hypothesized that transferred T cells were first primed in the MLN before proceeding to the lamina propria.

The priming event that was found to be required for driving colitis in this model is thought to involve OX40L. OX40L is a member of the TNF family, and OX40-OX40L interactions can enhance T-cell clonal expansion and cytokine production.75 High levels of OX40L positive CD11c+ CD11b+ CD8α− cells were identified in the MLN of colitic animals, and inhibiting the OX40-OX40L interaction in vivo using a blocking antibody resulted in ablation of disease.77 Interestingly, despite the accumulation of CD11c+ DC in the lamina propria of colitic mice, there was a distinct lack of OX40L expression, although OX40-positive T cells were present. These data suggested that T-cell encounter with activated DC in the MLN was crucial for the pathogenesis of disease.77 Most recently, B7-H1, a ligand for the programmed death-1 receptor (PD-1), has also been identified as playing a role in colitis because blockade of B7-H1 suppresses the development of disease in mice.78 In humans, PD-1 and B7-H1 positive mononuclear cells were increased in inflamed mucosa from patients with UC and CD, compared with normal controls.

Other groups studying DC phenotype and expansion in murine colitis models have demonstrated expansion of colonic lamina propria DC that exhibit up-regulated costimulatory molecule expression, such as CD40, CD80, and CD86.79 Analysis of cytokine expression by these DC from inflamed lamina propria following CD40 ligation showed increased levels of IL-12p40, IL-23p19, and IL-10. The DC from colitic lamina propria induced IFN-γ from cocultured NKT cells, but not IL-4 and IL-13, which was seen from mucosal DC from noncolitic mice. In humans, up-regulated expression of costimulatory molecules in diseased mucosal tissues from patients has been demonstrated by immunohistochemistry. Furthermore, DC isolated from the lamina propria of such individuals were shown to express higher levels of CD40 than those isolated from normal healthy tissues (reviewed in Stagg et al.53). Thus, DC activation status appears to be a contributing factor in generation of IBD both in mouse and in humans, and identifying a means to interrupt the activation of DC in vivo may be key to controlling this disease.

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Conclusion 

When discussing the role of DC and DC subsets in the intestinal immune system, we should make a cautionary note. The influence of a variety of different parameters, including antigen dose; T-cell cross-talk; local cytokine, chemokine, or metabolite production; signals through pathogen interactions; and local tissue microenvironment, just to name a few, are likely to have the ability to influence the outcome of T-cell priming by DC populations. Thus, it is increasingly obvious that we must approach inserting phenotypically distinct DC into functional pigeonholes with caution. As more data becomes available in both animal models and human disease systems, we hope to build a clearer picture of the functional contribution of DC populations to immunity, tolerance, and disease, thereby identifying key players that control the outcome of GI DC interaction with T cells.

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PII: S0016-5085(04)00102-7

doi:10.1053/j.gastro.2004.01.028

Gastroenterology
Volume 127, Issue 1 , Pages 300-309, July 2004

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