THEMES
Mucosal Immunity and Inflammation
I. Mucosal dendritic cells: their specialized role in initiating T cell responses*

Akiko Iwasaki and Brian L. Kelsall

Mucosal Immunity Section, Laboratory of Clinical Investigation, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892-1890


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Dendritic cells (DCs) are the most competent antigen-presenting cells known for the induction of primary T cell responses. Functional studies of tissue-resident DCs have been impaired by the rarity of these cells in any given organ. Recent development of isolation procedures allowing extraction of highly purified fresh DC populations has made it possible to study mucosal DCs in distinct mucosa-associated lymphoid tissues. Here, we discuss several recent studies by us and others that describe the tissue-specific phenotype and function of mucosal DCs and speculate on the mechanism by which the resident DCs regulate tissue-specific T cell responses.

type 1 T helper cell; type 2 T helper cell; interleukin-12; interleukin-10; interleukin-4


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DENDRITIC CELLS (DCs) have now been clearly shown to be the most competent professional antigen-presenting cells (APCs; reviewed in Ref. 1). DCs develop from bone marrow precursors and are sparsely distributed throughout both lymphoid and nonlymphoid organs. Tissue-resident DCs in their immature state are efficient in phagocytosis of incoming antigens. When subjected to microbial stimulation, antigen-loaded DCs migrate to the draining lymph nodes. On route, DCs process ingested antigens and present the fragmented peptides on their surface major histocompatibility complex (MHC) molecules. They also undergo functional maturation and upregulation of surface molecules important for T cell activation, such as CD80, CD86, and MHC class II.


    DISTRIBUTION AND PHENOTYPE OF DENDRITIC CELLS IN THE MUCOSA
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A number of immunohistological studies have revealed the presence of DC populations in various mucosa-associated lymphoid tissues (MALTs). In the gut-associated lymphoid tissues, DCs are found in the Peyer's patch, lamina propria, and draining mesenteric lymph nodes. Our immunohistochemical analysis of the Peyer's patches in the mouse has revealed two distinct populations of DCs (9). One subset of DCs is located immediately underneath the follicle-associated epithelium in the subepithelial dome (SED), and they express the DC surface antigen CD11c but not the variant mannose receptor DEC-205, nor the intracellular antigen recognized by antibody M342. DCs with this staining pattern are also found scattered throughout the B cell follicle but are excluded from germinal centers. The DCs in the SED are anatomically ideally situated for taking up luminal antigens transported by M cells. Similar MHC class II-expressing cells with dendritic morphology have been found in the Peyer's patch SED region of both humans and rats. The other subset of DCs is present in the interfollicular regions (IFR) in close association with T cells. These DCs express CD11c and DEC-205 and stain with M342. The expression of DEC-205, as well as the antigen recognized by M342, has correlated with DC maturation in vitro, and these antigens are expressed by interdigitating DCs from other lymphoid organs, suggesting that the IFR DCs are more mature or differentiated than those in the SED. The IFR DCs are most likely responsible for priming T cells, since they come in close contact with naive T cells, much like the interdigitating DCs in the lymph nodes. However, because T cells are present throughout the Peyer's patch, the possibility of primary or secondary T cell activation by DCs in the SED or B cell follicle cannot be ruled out.

Ruedl and Hubele (17) showed that freshly isolated CD11c+ cells from Peyer's patches phagocytose particulate antigens and efficiently process soluble antigens. When subjected to overnight culture in the presence of either granulocyte macrophage-colony stimulating factor (GM-CSF) and tumor necrosis factor-alpha or anti-CD40 antibody, Peyer's patch DCs undergo maturation and express higher levels of MHC class II, CD80, and CD86 and lose their ability to process intact antigens. In addition, the vast majority of Peyer's patch DCs did not express DEC-205 when freshly isolated but expressed this marker when cultured with anti-CD40. Thus freshly isolated CD11c+ Peyer's patch DCs in these studies were phenotypically and functionally immature and thus likely represent the CD11c+-DEC-205- population described above.

DCs have also been found in diffuse lymphoid tissues of the intestine. In the lamina propria, we and others have found DCs present throughout the small and large intestine of the mouse and human. Detailed functional studies of DCs from the lamina propria, however, are lacking. A recent study by Maric et al. (11) has identified a new population of DCs in the rat intestinal epithelium. With the use of a novel fixation technique, MHC class II+ cells with DC morphology whose processes crossed the basement membrane were observed (11). Whether these DCs are present in other species and whether they directly sample intestinal antigens and present them to T cells in their vicinity remain to be determined.

In the respiratory mucosa, DCs have been shown to be the principal resident APCs of the rat, mouse, and human lung (reviewed in Ref. 16). DC populations in the lung can be found both in the airway epithelium and within the underlying mucosa. Within the unperturbed airway epithelium, DCs form a tightly meshed network that resembles epidermal Langerhans cells. Moreover, DCs are rapidly recruited to the airway epithelia following intranasal administration of various stimuli (15). The peak increase in the number of DCs in the lung epithelium occurred within 2 h after the injection of microbial stimuli, and emigration of the DCs to the draining lymph nodes followed for the ensuing 48 h. Much like skin Langerhans cells and Peyer's patch DCs, an overnight incubation of freshly isolated lung epithelial DCs increases their antigen-presenting capability.


    T CELL RESPONSES FOLLOWING MUCOSAL ANTIGEN DELIVERY
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The mucosal microenvironment appears to be particularly geared toward the induction of T helper cells producing type 2 [interleukin (IL)-4, IL-5, and IL-10; Th2] and type 3 [transforming growth factor-beta (TGF-beta ); Th3] cytokines. This particular ability would be consistent with the two prominent, unique features of immune responses to oral antigens: the production of IgA and the induction of regulatory cell-mediated oral tolerance. Thus it has been shown that efficient B cell isotype switching to IgA depends on both T cells and the presence of cytokines such as IL-4, IL-5, IL-10, and TGF-beta (reviewed in Ref. 13). In addition, administration of soluble protein antigens into the gut and airway mucosa leads to induction of systemic immunological tolerance (reviewed in Ref. 21). Such oral tolerance is mediated by anergy or apoptosis of antigen-specific lymphocytes following injection of a large dose (typically >10 mg) of antigen. However, repeated feeding of low doses of antigen (typically 0.2-5 mg/feeding) results in the induction of regulatory T cells, which are thought to migrate to systemic sites and secrete cytokines such as IL-4, IL-10 (Th2), and TGF-beta (Th3) following reencounter with antigen. These suppressive cytokines can downregulate interferon-gamma (IFN-gamma )-mediated (Th1) T cell responses not only to the fed antigen but to unrelated antigens as well. Finally, it makes sense that mucosal tissues would be geared to the induction of T cells that produce non- or anti-inflammatory cytokines, since the T helper cell balance in the intestinal mucosa seems crucial for the maintenance of its own immunological homeostasis. Thus it has now been demonstrated in a number of murine models that an uninhibited local Th1 response to endogenous bacterial antigens results in extensive inflammation in the bowel (6).

More direct evidence that distinct T cell responses to certain antigens can be induced depending on the route of antigen delivery is limited. For example, it has been shown that oral administration of sheep red blood cells into mice leads to the production of Th2 cytokines from Peyer's patch T cells, whereas systemic injection of the same antigen results in the induction of Th1 response in the spleen (23). In addition, responses to cholera toxin and protein immunization are more Th2 oriented when given by the oral route (24). However, interpretation of these responses to immunization with cholera toxin with respect to understanding the normal mucosal environment is complicated by the fact that cholera toxin is able to suppress the production of IL-12 from monocytes and DCs (3), which would directly influence T cell differentiation. It has also been shown that antigens encountered by the respiratory mucosal surfaces result in the initial generation of Th2 responses in the draining lymph nodes (14). These studies thus support the hypothesis that MALTs are particularly capable of generating Th2 CD4+ T cell responses when challenged with protein antigens.

Despite this ability to generate Th2/Th3 responses in MALTs, however, distinct Th1-responses can be induced in the mucosa, particularly following intestinal infection with pathogenic microorganisms. For instance, IFN-gamma secretion by Peyer's patch T cells has been observed after gastrointestinal infection with Salmonella typhimurium (8) and Toxoplasma gondii (10). Finally, it has been shown that very high doses of a soluble antigen (ovalbumin) given orally to ovalbumin T cell receptor (TCR)-transgenic mice (4, 12) or to mice to which T cells from ovalbumin TCR-transgenic mice were transferred (5) resulted in the induction of a predominant Th1 T cell response, which was rapidly followed by T cell deletion. In contrast, after multiple low doses of ovalbumin, the T cell response was predominated by Th2/Th3 cytokines (4, 5). Thus, under conditions of single high-dose antigen exposure, Th1 responses can occur as a prelude to deletion.


    ROLE OF MUCOSAL DENDRITIC CELLS IN DIRECTING T HELPER CELL RESPONSES
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The particular reasons why the mucosal environment may be especially conducive to the differentiation of T cells into a Th2/Th3 pathway are unclear. One possibility is the presence of distinct APCs capable of Th2 induction in the mucosa. Because DCs are the most potent APCs known, we have examined their role in directing T cell responses in both mucosal (Peyer's patch) and systemic (spleen) tissues (unpublished observations). To study the function of unmanipulated DC populations from these organs, we employed a magnetic bead-based DC isolation procedure that does not require stimulation in vitro. We further purified DCs based on the CD11c expression by flow cytometric cell sorting. Highly purified DCs isolated in this manner were assessed for their ability to prime antigen-specific naive T cells from TCR-transgenic mice on two different genetic backgrounds. Remarkably, stimulation of naive T cells by Peyer's patch DCs induced the differentiation of T cells that, on secondary stimulation in vitro with anti-CD3 and anti-CD28, produced high levels of IL-4 and IL-10 and lower levels of IFN-gamma compared with T cells primed with spleen DCs, which produced predominantly IFN-gamma . These studies suggested that there is a primary difference between DCs from the Peyer's patch and those from spleen that translates to their ability to induce distinct T cell responses.

In an effort to decipher the mechanism of Th2 and Th1 induction by Peyer's patch DC and spleen DC, respectively, we initially performed priming cultures in the presence of antibodies to IL-10 or TGF-beta , two cytokines produced by APCs that have direct effects on the Th1/Th2 differentiation. We found that IFN-gamma production by Peyer's patch DC-primed T cells was enhanced by the addition of neutralizing antibody against either TGF-beta or IL-10 to the priming cultures, whereas we found no effect of either antibody on IFN-gamma production by T cells primed with spleen DCs. These findings suggested either that TGF-beta and IL-10 may be secreted by Peyer's patch and not spleen DCs or that Peyer's patch and not spleen DCs induced T cells to secrete TGF-beta and IL-10, which in turn suppressed the differentiation of Th1 T cell responses.

To explore this issue more directly, we next characterized cytokine production by DCs following the direct ligation of CD40 with a trimerized recombinant form of CD40L, a molecule normally expressed on activated T cells. Interestingly, Peyer's patch DCs but not spleen DCs secreted IL-10 after overnight stimulation with CD40L trimer. On the other hand, the levels of IL-12 p40 secreted by these DCs were comparable. Unfortunately, the levels of TGF-beta produced could not be assessed, since the DCs did not survive culture in serum-free medium.

Taken together, these studies establish the hypothesis that IL-10 and possibly TGF-beta are produced by Peyer's patch DCs when interaction with naive T cells occurs and that these cytokines either directly or indirectly drive T cells to differentiate into T cells producing Th2 cytokines and TGF-beta . In support of this possibility, IL-10 has been shown not only to play an indirect role in the differentiation of Th2 cells, i.e., via the inhibition of IL-12 production by APCs, but also to act as a critical factor in the development of T regulatory type 1 (Tr1) cells. These cells have been recently reported to be capable of suppressing inflammation in the gut by the secretion of IL-10 and TGF-beta (7). Although our in vitro culture system failed to detect distinct Tr1 cells induced by Peyer's patch DCs, as we could not detect production of TGF-beta in secondary cultures, it remains an intriguing possibility that such cells are induced in the gut mucosa where high levels of endogenous IL-10 are present. In addition, in studies of T cell differentiation in vitro, it has recently been shown that either IL-10 or TGF-beta itself will prime T cells for the production of TGF-beta (20).

Finally, recent studies by Stumbles et al. (22) provide direct support for the hypothesis that mucosal DCs can drive distinct T cell differentiation pathways. They found that rat respiratory tract DCs induce Th2 responses in vivo. After adoptive transfer of freshly isolated, antigen-pulsed respiratory tract DCs, preferential induction of Th2-dependent antibody and T cell responses was observed. However, if the respiratory tract DCs were precultured with GM-CSF, Th1-dependent antibody responses prevailed following adoptive transfer. Thus this study along with our data suggests that mucosal resident DCs have a propensity for inducing Th2 responses, unless activated by a maturation signal.


    HYPOTHESIS FOR THE INDUCTION OF T CELL RESPONSES AT MUCOSAL SITES
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Taking the above-mentioned studies into consideration, we propose the following hypothesis for immune induction at mucosal sites (see Fig. 1). In the gut mucosa, SED DCs take up intestinal antigens transported via M cells and migrate to the T cell regions and become IFR DCs. During migration, SED DCs can undergo two distinct developmental pathways. If the antigen encountered is a noninfectious food antigen, the default pathway for IFR DCs is to generate Th2 and/or Th3 responses through secretion of high levels of IL-10 and TGF-beta and low levels of IL-12. However, when encounters with microbial stimuli occur, such as double-stranded RNA or lipopolysaccharides (danger signals), conventional maturation of DCs is triggered. This maturation of DCs leads to secretion of high levels of IL-12, which induces T cells to secrete IFN-gamma resulting in Th1 responses. In support of this hypothesis, Th1 responses are induced following oral inoculation of microorganisms that are known to induce IL-12 secretion from macrophages or DCs (8, 10). Similarly, in the airway mucosa, innocuous antigens are taken up by resident epithelial DCs. Antigen-loaded DCs migrate to the draining lymph nodes and induce Th2 or Th3 responses. When encounters with microbial pathogens occur, however, rapid recruitment of new DC populations occurs at the epithelium (15). The DCs take up the pathogen and migrate to the draining lymph nodes where they induce a potent Th1 response through secretion of IL-12 (22).


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Fig. 1.   Hypothetical role for dendritic cells (DCs) in the induction of T cell responses in the Peyer's patch. According to this model, DCs can undergo 2 distinct pathways of differentiation in the Peyer's patch, depending on the type of antigen encountered (see text for further discussion). One pathway promotes DCs to produce interleukin (IL)-10 and transforming growth factor-beta (TGF-beta ) but little IL-12 p70; interaction of these DCs with naive T cells (Tn) drives the differentiation of T helper type 2 (Th2) as well as Th3 and/or T regulatory type 1 (Tr1) cells (DC2). This would occur as a default pathway with innocuous protein antigens. In contrast, when a signal is received from an invading pathogen, Peyer's patch DCs produce high levels of IL-12 p70 but low levels of IL-10 and TGF-beta , and these DCs drive the differentiation of Th1 cells (DC1). This may also occur with high-dose antigen administration for reasons that are not yet clear. Correlated with this enhanced ability to produce IL-12, microbial stimulation could result in DC maturation/differentiation and movement of DCs into T cell regions [interfollicular regions (IFR)] of the Peyer's patch, whereas the less differentiated DCs in the subepithelial dome (SED) could drive T cell differentiation in the SED or follicle. However, given the small number of T cells in the SED or the follicle, to interact with DCs, it is more likely that both DC1 and DC2 populations differentiate along different pathways with respect to cytokine production and stimulate distinct T-helper responses in the T cell region.


    FUTURE DIRECTIONS AND CLINICAL IMPLICATIONS
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Although the intricate immune induction mechanism at mucosal sites is just beginning to unfold, there remain many fundamental questions that must be addressed by future investigation. First and foremost is the determination of the mechanism underlying the unique ability of resting mucosal DCs to prime Th2 responses. As we have shown for IL-10, other humoral factors such as cytokines and chemokines may be involved in the development of the Th2 phenotype. Recent studies have shown that CCR3 (18) and CXCR3 (2) are expressed more or less selectively by Th2 and Th1 cells, respectively. Whether the ligands for these and other chemokine receptors are expressed differentially by mucosal vs. systemic DCs requires future investigation. Moreover, cell surface molecules may play a role in determining the outcome of T helper responses induced by distinct DC subsets. Obvious candidates are the costimulatory molecules CD80 and CD86. Although freshly isolated Peyer's patch DCs and spleen DCs expressed comparably low levels of these molecules, when activated these cells may differentially regulate the level and/or duration of surface expression of costimulatory molecules. Selective engagement of immunostimulatory CD28 or inhibitory cytotoxic T lymphocyte-associated molecule-4 (CTLA-4) on T cells by CD80 or CD86 molecules may influence the T-helper phenotype. However, the precise nature of the complex interplay between costimulatory molecules CD80 and CD86 expressed on APCs and their ligands CD28 and CTLA-4 on T cells, which occur during an immune response in vivo, remains to be determined. Alternatively, adhesion molecules expressed by distinct DCs could influence the phenotype of T cells induced. Recently, a Th2-inhibitory role of the adhesion molecules intercellular adhesion molecule (ICAM)-1 and ICAM-2 and lymphocyte function-associated antigen-1 has been demonstrated in DC priming of antigen-specific T cells (19).

The mechanistic insights provided by characterization of mucosal DCs will undoubtedly advance strategies for mucosal vaccine design. Current experimental approaches to induction of effective mucosal immunity include delivery of antigens in adjuvant such as cholera toxin. Coadministration of cholera toxin and antigen often results in a local Th2 response with increased production of IL-4, IL-5, and IL-10. It is now possible to investigate the in vivo mechanism for the immunostimulatory activity of cholera toxin and other mucosal adjuvants on DCs and its effect in modulating DCs to selectively prime Th2 cells. Finally, strategies to enhance oral tolerance by manipulating local DCs, specifically to enhance Th3/Tr1 responses, need to be explored for treatment of a number of autoimmune diseases.


    FOOTNOTES

* First in a series of invited articles on Mucosal Immunity and Inflammation.

Address for reprint requests and other correspondence: B. L. Kelsall, National Institutes of Health, Bldg. 10, Room 11N238, 10 Center Dr., Bethesda, MD 20892-1890 (E-mail: kelsall{at}nih.gov).


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Am J Physiol Gastroint Liver Physiol 276(5):G1074-G1078