Inflammatory bowel diseases (IBDs) including Crohn’s disease and ulcerative colitis represent a major challenge to clinicians and immunologists trying to understand why in certain individuals the peaceful coexistence of the commensal microflora and its host breaks down and results in chronic inflammation. The recent progress in our understanding of the organization of the intestinal mononuclear phagocytes with dendritic cells and macrophages of distinct phenotype, origin and function. The potential strategies to translate the recent findings into the management of chronic inflammation in animal models of IBD.
The digestive tract has a surface area nearly 200 times greater than that of the skin. Being an important port of entry for microorganisms, the gut must be protected by effective immune responses. However, immune reactivity must be prevented from damaging gut tissues in response to benign foreign material to which the gut is continuously exposed. T cell immunity relies on the recognition of antigenic peptides processed and presented to T cells by dendritic cells (DCs), which act as initiators, stimulators and regulators of antigen-specific T cell responses, but also play a pivotal role in the maintenance of tolerance towards the commensal microflora.
DCs are specialized accessory cells distinguishable from other mononuclear phagocytes (MPs) such as monocytes and macrophages by their unique morphology and ability to capture and process antigens for presentation to effector T cells. Upon encounter with pathogens and activation, DCs undergo rapid maturation characterized by the upregulation of major histocompatibility complex (MHC) and costimulatory molecules and migrate to the draining lymph nodes. The remarkable flexibility of DC functions likely results from their ability to sense the local environment and to shape the ensuing immune response. Intestinal MPs are distributed in organized lymphoid organs, such as Peyer’s patches (PP) and mesenteric lymph nodes (MLN), and are highly abundant in the loose connective tissue underlying the epithelium, the lamina propria (LP).
It is now established that DCs play a crucial role in both immunity and tolerance. In a tolerogenic setting, DC can induce anergy in antigen-specific T cells or generate protective FoxP3+ regulatory T cells (Treg) in the lymph nodes. Under steady-state conditions, DCs continuously migrate from peripheral organs via the lymph to secondary lymphoid organs, where they present self-antigens or innocuous environmental antigens to maintain peripheral tolerance. The chemokine receptor, CCR7, is a key regulator of the homeostatic and inflammation-induced trafficking of DCs from skin, lung and gut to their respective draining lymph nodes
Dendritic cells (DCs) program local immune responses by priming naive T cells and driving their differentiation. Murine DCs have been divided into plasmacytoid (B220+) and conventional (CD4−CD8+, CD8−CD4+, and double-negative [DN] CD8−CD4−) subsets. Although several DC subsets were described as having a specific function, DCs are characterized by high plasticity among subsets. Local tissue-derived factors seem to have an impact on the phenotype and function of DCs. In the intestine, DCs reside in the lamina propria (LP) of the small intestine (siLP) and the colon (cLP), isolated lymph follicles, Peyer’s patches, and mesenteric lymph nodes (MLNs). CD103+ (the αE chain of the αEβ7 integrin) siLP DCs are potent inducers of homing receptors (CCR9 and the α4β7 integrin) on (CD4 and CD8) T and IgA+ B cells. These subsets have the enhanced capacity to induce the differentiation of Foxp3-expressing regulatory T (Treg) cells. In part, this process is driven by the vitamin A metabolite retinoic acid.
CX3CR1+ DCs are closely associated with the epithelial lining (13). CX3CR1+ binds fractalkine/CX3CL1, which is expressed (in a soluble and a membrane-bound form) by intestinal epithelial and endothelial cells . In the particular case of the intestine, DCs play a central role in sampling and processing luminal Ags. CX3CR1+ DCs extend transepithelial dendrites into the gut lumen to sample and process luminal Ags. CX3CR1+ DCs initiate the host defense to intestinal pathogens, such as Salmonella, as shown by the enhanced susceptibility of CX3CR1-deficient animals to Salmonella infection. Interactions of DCs with T cells can mediate adaptive immunity required for the clearance of pathogens. Macrophage-derived IL-10 controls the production of proinflammatory cytokines by CX3CR1+ DCs.
Intestinal CD11c+ subsets based on CD103 and CX3CR1 expression. The CD11c+ population in the cLP consists of CD68−CX3CR1+, CD103+, and CD103−CX3CR1− DCs and CD68+CX3CR1+ macrophages. CX3CR1+CD11c+ cells expand in the gut in response to the enteric flora. Whether these cLP DCs and macrophages program a regulatory or proinflammatory phenotype in CD4 T cells that they specifically activate was examined in vitro and in vivo. The data indicated that the local accumulation of CX3CR1+ DCs depends on the enteric flora supporting inflammatory immune responses
Intestinal dendritic cells in the pathogenesis of inflammatory bowel disease.
The gastrointestinal tract harbors a large number and diverse array of commensal bacteria and is an important entry site for pathogens. For these reasons, the intestinal immune system is uniquely dedicated to protect against infections, while avoiding the development of destructive inflammatory responses to the microbiota. Human inflammatory bowel disease (IBD) consists of 2 dominant disease subtypes, Crohn’s disease (CD), largely arising from a Th1 response, and ulcerative colitis (UC), largely mediated by interleukin (IL)-5- and IL-13-producing T cells or natural killer T cells. The immunopathology of human IBD relates to an inappropriate and exaggerated immune response to constituents of the gut flora in a genetically predisposed individual. Amongst other cell types, DCs play a role in IBD pathogenesis, as suggested by mouse models of colitis and by observations in humans. The local microenvironment regulates the function of mucosal DCs through the presence of immune cells, non-immune cells and luminal bacteria. In principle, DC dysfunction may promote the development of gut inflammation by priming T-cell responses against bacteria, by sustaining T cell reactivity within the inflamed mucosa and by functioning as effector cells releasing proinflammatory cytokinesSeveral models have been proposed to explain how the immune system discriminates between, and appropriately responds to, commensal and pathogenic microorganisms. Dendritic cells (DCs) and regulatory T cells (Treg) are instrumental in maintaining immune homeostasis and tolerance in the gut. DCs are virtually omnipresent and are remarkably plastic, having the ability to adapt to the influences of the microenvironment. Different DC populations with partially overlapping phenotypic and functional properties have been described in different anatomical locations. DCs in the draining mesenteric lymph nodes, in the intestinal lamina propria and in Peyer’s patches partake both in the control of intestinal inflammation and in the maintenance of gut tolerance.In this respect, gut-resident DCs and macrophages exert tolerogenic functions as they regularly encounter and sense commensal bacteria. In contrast, migrating DC subsets that are recruited to the gut as a result of pathogenic insults initiate immune responses. Importantly, tolerogenic DCs act by promoting the differentiation and expansion of Treg cells that efficiently modulate gut inflammation, as shown both in pre-clinical models of colitis and in patients with inflammatory bowel disease (IBD). The phenotypic and functional features of gut DC subsets and discusses the current evidence underpinning the DC contribution to the pathogenesis of the major clinical subtypes of human IBD. It also addresses the potential clinical benefit derived from DC targeting either in vivo or in vitro.
Mechanisms Underlying DC-Mediated Tolerance in The Gut
One of the major functions of tolerogenic DCs may be the differentiation of Treg cells from naïve T cells. Two major subtypes of Treg cells have been described to date, namely, naturally occurring CD4+CD25+FoxP3+ Treg cells (nTreg) and inducible type 1 Treg cells (Tr1).
DCs as inducers of nTreg cells
Naturally occurring Treg cells, a functionally specialized subset of CD4+ T cells, have been involved in preventing T cell-mediated and innate immune pathology in a number of disease models. The transcription factor FoxP3 is expressed by CD4+CD25+ Treg cells and is fundamental for Treg development and function. nTreg cells mainly suppress effector T cells through a cell contact-dependent and largely contact-independent mechanism. Membrane-bound transforming growth factor (TGF)-β has been implicated in nTreg-mediated inhibition of T cell responses. Moreover, TGF-β1 acts as a co-stimulatory factor for FoxP3 expression, leading to Treg differentiation from CD4+CD25– T cells. Interestingly, TGF-β1 production by Treg cells is not required for inhibition of colitis, suggesting that Treg cells may induce TGF-β release by other hematopoietic or stromal cells. Support for this hypothesis is provided by the observation that suppression of colitis by TGF-β1-/- Treg cells was inhibited by anti-TGF-β antibodies, indicating that TGF-β is central to the function of Treg cells even when they do not synthesize it themselves. In this respect, DCs remain a key and intriguing candidate for TGF-β production in vivo. It is conceivable that Treg cells be required to express TGF-β1 on the cell surface and to present it to pathogenic T cells, as previously shown.
Treg cells are believed to play a crucial role in inhibiting intestinal inflammation and IBD. Notably, Treg cells may contribute differentially to the modulation of experimental autoimmune gastritis and colitis. Protection from colitis, but not from gastric inflammation, has been reported to depend on IL-10 expression by CD4+CD25+ nTreg cells. The T cell transfer model of colitis allows an understanding of Treg-mediated mechanisms controlling intestinal inflammation. During cure of experimental colitis, Treg cells proliferate and accumulate in MLN and colonic LP, in contact with CD11c+ DCs and effector T cells. Interestingly, IL-10-producing Treg cells selectively enrich within the colonic LP, whereas FoxP3-expressing Treg cells are present in similar frequencies in both the secondary lymphoid organs and LP of colitic animals. Transfer of CD4+CD45RB+ T cells into RAG-/- mice causes colitis. Disease development requires β7-integrin-dependent intestinal localization. Importantly, β7-deficient Treg cells prevent colitis, suggesting that Treg accumulation in the intestine is dispensable for disease suppression. The presence of Treg cells impacts on CD4+CD45RB+ T cell accumulation in the intestine, indicating that one major function of Treg cells may involve the inhibition of tissue localization of Th1 effector cells.
Peripheral blood CD4+CD25high T cells may be decreased in active human IBD compared with inactive disease. Notably, Treg cells are increased in mucosal IBD lesions, coincident with an increase in transcripts for IL-8, a hallmark of inflammation in the gut, and for FoxP3. The higher degree of Treg infiltration in the gut LP of patients with diverticulitis compared with IBD suggests that an insufficient increase of Treg cells in IBD accounts for inflammation and intestinal pathology. In the LP of human colon, Treg accumulation has been detected in a variety of inflammatory conditions, such as diverticulitis, pseudo-membranous colitis and cytomegalovirus-induced colitis, and may not be a specific feature of CD or UC. The presence of FoxP3+ T cells in the LP of patients with IBD suggests that defects in Treg numbers may not account for the pathology, and that ineffective Treg activity may rather contribute to sustained gut inflammation.
DCs as inducers of Tr1 cells
Tr1 have been described as a CD4+ T-cell subset releasing high levels of IL-10, in the absence of measurable IL-2 and IL-4 production, and exerting suppressive functions in an IL-10/TGF-β-dependent but cell contact-independent manner. The production and release of interferon (IFN)-γ and TGF-β by Tr1 cells are comparable with those of Th0 and Th1 clones, respectively. Colitis in the severe combined immunodeficient (SCID) mouse model involves the development of Th1 cells responding primarily to the intestinal flora. The transfer of ovalbumin (OVA)-specific Tr1 cells in SCID mice with CD4+CD45RBhi T cell-induced colitis prevents disease manifestations, an effect that is dependent upon the in vivo activation of Tr1 cells by feeding mice with OVA. This observation indicates that Tr1 cells can inhibit immune responses to unknown antigens by a bystander suppression mechanism. Another report has shown that IL-10-/- mice lack CD4+CD45RBlo Treg cells capable of controlling intestinal inflammatory responses, pointing to IL-10 as a crucial mediator of tolerance in the gut. Similarly, TGF-β is required to suppress Th1-mediated colitis induced by CD4+CD45RBhi T cells, indicating that IL-10 and TGF-β play non-redundant roles in the functioning of intestinal Treg cells.
The source of IL-10 which regulates colitis remains to be unequivocally identified. Treg-derived IL-10 was recently shown to be dispensable for suppression of colitis in Rag1-/- mice, but host IL-10 was required to inhibit disease development. Specifically, IL-10 production by myeloid CD11b+F4/80+ cells, mostly macrophages, was important for the maintenance of Foxp3 expression by Treg cells. IL-10 acted directly on Treg cells, because Treg cells lacking IL-10Rβ chain failed to suppress colitis when transferred together with CD4+CD45RBhi T cells. In addition, this study demonstrates that IL-10 is not required to maintain FoxP3 expression in non-inflammatory conditions, because Treg development and function are unaffected in Il10rb-/- mice. It is conceivable that the differential requirement for IL-10 for FoxP3 expression and maintenance in inflammatory vs non-inflammatory conditions may reflect the need for an additional signal to counter inflammatory mediators such as IL-6 or tumor necrosis factor (TNF)-α. It remains to be determined whether IL-10-mediated mechanisms are unique to the gut microenvironment or whether IL-10 may be required to maintain FoxP3 expression in other organs.
Other studies pointed to Treg-derived IL-10 as a major contributor to Treg-mediated suppression. These discrepancies may be attributed to differences in the endogenous flora and/or in the model systems studied. Mucosal CD8α+ DCs with a CD11cloB220+ phenotype can be isolated from mouse MLN and have been reported to promote the suppressive function of CD4+CD25+ Treg cells and to promote the conversion of naïve T cells into Tr1-like cells. At variance with classical Tr1 cells, the Tr1-like cells described in this study released IL-10, IL-4 and IFN-γ and suppressed T helper proliferation. The CD8α+ DC were capable of supporting Tr1-like cell differentiation also in the presence of a maturational stimulus, such as CpG, as reported for other tolerogenic, semi-mature DC preparations.
DC expression of indoleamine 2,3-dioxygenase 1 and gut tolerance
Indoleamine 2,3-dioxygenase 1 (IDO1) is a tryptophan-catabolizing enzyme implicated in maternal allograft acceptance and in immune tolerance to tumors. IDO1 converts tryptophan into immune suppressive kynurenines that profoundly affect T-cell functions, promoting T-cell unresponsiveness, T-cell apoptosis and differentiation of Treg cells. IDO expression has been associated with CD103+ DCs in the gut LP and MLN of mice. Similarly, human intestinal CD11c+CD103+ DCs express higher levels of IDO mRNA compared with CD11c+CD103– DCs. IDO inhibition of mouse CD103+ DCs with the d isomer of 1-methyl-tryptophan (1MT) reduced the ability of IDO+ DCs to convert Treg cells and augmented the generation of IL-17-producing T cells. Mice treated with 1MT concomitant with adoptive transfer of OVA transgenic T cells and oral immunization with OVA led to a reduction in the frequency of Treg cells in the LP, PP and MLN. Ido1-/- mice displayed a decreased percentage of Foxp3+ Treg cells in the LP and an almost double the proportion of IL-17+CD4+ and IFN-γ+CD4+ T cells in the intestine compared with wild-type animals. Finally, Rag1-/- mice injected with colitogenic T cells from C57BL/6 mice experienced more extensive gut inflammation and aggressive disease if treated with 1MT. Similar effects were demonstrated in mice with dextran sodium sulfate (DSS)-colitis, where 1MT administration worsened the mortality rate and colon shortening. Collectively, these experiments indicate that IDO may play a previously unappreciated and fundamental role in regulating gut inflammation through the control of Th1/Th17/Treg balance.
The expression of IDO in the murine gut may increase with age via an IFN-γ-dependent mechanism that involves commensal microorganisms. IDO-deficient mice have abnormally high levels of both IgG and IgA, a phenomenon driven by the commensal flora. IDO may then physiologically restrict B-cell responses to intestinal commensal bacteria. The elevated levels of IgG and IgA in IDO-deficient mice might in principle confer resistance to enteric pathogens such as Citrobacter rodentium, a gram-negative bacillus similar to human enteropathogenic Escherichia coli. When infected orally with Citrobacter, IDO-deficient mice appeared well throughout the course of the experiment, at variance with wild-type animals that had decreased activity, ruffled fur and hunched posture, and had attenuated gut colonization by the pathogen. IDO-deficient mice had reduced edema, inflammatory cell infiltration and epithelial damage in colonic tissue sections, associated with lower levels of TNF-α compared with wild-type mice. These observations point to IDO as a novel target to manipulate intestinal inflammation and to control diseases caused by enteric pathogens.
Crosstalk between DCs and intestinal epithelial cells
Intestinal epithelial cells (IECs) are a central component of the immune system of the gut. They express receptors for microbial-associated molecular patterns that activate signaling cascades leading to the production of antimicrobial products and chemokines. IECs can also recruit leukocytes to complement their barrier function or to participate in the activation of gut adaptive immune responses, including the production of IgA and the differentiation of effector Th1, Th2 and Th17 cells.
IECs are in close contact with LP DCs and have been shown to release molecules that influence DC functions. Thymic stromal lymphopoietin (TSLP) is a cytokine secreted by IECs under steady-state conditions and imparts a Th2-polarizing phenotype to DCs. IEC-derived factors also stimulate the expression of both chains of TSLP receptor on DCs, namely the common IL-7 receptor α chain and the TSLP receptor, thus conferring the ability to respond to TSLP and to drive Th2 responses. Importantly, TSLP expression by primary IECs may be deregulated in a proportion of patients with IBD. The same study also showed that mRNA signals for TSLP are readily detected in IECs from healthy controls, although the protein is consistently below the detection limit by immunoprecipitation, unless IECs are challenged with bacteria such as S. typhimurium. TSLP has been detected in epithelial cells of the Hassall’s corpuscles and activates myeloid CD11c+ DCs in the thymic medulla. These apparently mature DCs promote the development of Treg cells through a mechanism that requires peptide-MHC class II interactions, and the presence of CD80, CD86 and IL-2. Plasmacytoid DCs can be also activated by TSLP and become efficient generators of Treg cells from thymocytes through an IL-10-dependent mechanism. CD4+ T cells triggered through the T cell receptor, but not resting CD4+ T cells, respond to TSLP with robust proliferation and acquire sensitivity to low doses of IL-2
Enteric flora expands gut lamina propria CX3CR1+ dendritic cells supporting inflammatory immune responses
CD103 or CX(3)CR1 surface expression defines distinct dendritic cells (DCs) and macrophages in the murine lamina propria of the colon (cLP). We investigated the surface marker and functional phenotype of CD103(+) and CX(3)CR1(+) cLP DCs and their role in transfer colitis. cLP CD11c(+) cells were isolated from specific pathogen-free or germ-free mice to elucidate the role of the commensal flora in their development. The cLP CD11c(+) cells are a heterogeneous cell population that includes 16% CX(3)CR1(+), 34% CD103(+), 30% CD103(-)CX(3)CR1(-) DCs, and 17% CD68(+/)F4/80(+)CX(3)CR1(+)CD11c(+) macrophages. All DCs expressed high levels of MHC II but low levels of costimulatory (CD40, CD86, and CD80) and coinhibitory (programmed death ligand-1) molecules. Ex vivo confocal microscopy demonstrated that CX(3)CR1(+)CD11c(+) cells, but not CD103(+) DCs, were reduced in the cLP of germ-free (CX(3)CR1-GFP) mice. The absence of the enteric flora prevents the formation of transepithelial processes by the CX(3)CR1(+) DCs. CX(3)CR1(+) DCs preferentially supported Th1/Th17 CD4 T cell differentiation. CD103(+) DCs preferentially induced the differentiation of Foxp3-expressing regulatory T cells. The stimulation of cLP DCs with fractalkine/CX(3)CL1 increased the release of IL-6 and TNF-alpha. In the absence of CX(3)CR1, the CD45RB(high) CD4 transfer colitis was suppressed and associated with reduced numbers of DCs in the mesenteric lymph nodes and a reduction in serum IFN-gamma and IL-17. The local bacteria-driven accumulation of CX(3)CR1(+) DCs seems to support inflammatory immune responses.
Goblet cells deliver luminal antigen to CD103+ dendritic cells in the small intestine.
The intestinal immune system is exposed to a mixture of foreign antigens from diet, commensal flora and potential pathogens. Understanding how pathogen-specific immunity is elicited while avoiding inappropriate responses to the background of innocuous antigens is essential for understanding and treating intestinal infections and inflammatory diseases. The ingestion of protein antigen can induce oral tolerance, which is mediated in part by a subset of intestinal dendritic cells (DCs) that promote the development of regulatory T cells. The lamina propria (LP) underlies the expansive single-cell absorptive villous epithelium and contains a large population of DCs (CD11c(+) CD11b(+) MHCII(+) cells) comprised of two predominant subsets: CD103(+) CX(3)CR1(-) DCs, which promote IgA production, imprint gut homing on lymphocytes and induce the development of regulatory T cells, and CD103(-) CX(3)CR1(+) DCs (with features of macrophages), which promote tumour necrosis factor-α (TNF-α) production, colitis, and the development of T(H)17 T cells. However, the mechanisms by which different intestinal LP-DC subsets capture luminal antigens in vivo remains largely unexplored. Using a minimally disruptive in vivo imaging approach we show that in the steady state, small intestine goblet cells (GCs) function as passages delivering low molecular weight soluble antigens from the intestinal lumen to underlying CD103(+) LP-DCs. The preferential delivery of antigens to DCs with tolerogenic properties implies a key role for this GC function in intestinal immune homeostasis.
Human intestinal dendritic cells, gut microbiota, and disease activity in Crohn’s disease.
Crohn’s disease (CD) is a chronic gastrointestinal inflammatory disorder considered to be the result of an inappropriate and exaggerated mucosal immune reaction to yet undefined triggers from the gut flora in genetically predisposed individuals. This inflammatory phenomenon has been characterized by an adaptive T-cell response in addition to an abnormal function of the innate immune system. Dendritic cells (DCs) are constituents of this innate system, inducing T-cell activation via antigen presentation. In the gut, mucosal DCs are separated from the luminal milieu by a monolayer of cylindrical epithelial cells that forms an anatomical and physiological barrier that controls the normal traffic of antigens between both compartments. An imbalance of colonic and ileal DC distribution in tissues from CD patients as well as functional differences between DCs isolated from normal and diseased intestinal samples have been demonstrated. Moreover, a gut barrier defect in the para- and transepithelial routes in addition to a significant reduction in the intestinal secretion of epithelial products involved in barrier function has been well documented in CD. Therefore, this may expose the diseased mucosa to overwhelming amounts of antigens, resulting in abnormal DC activation and a subsequent imbalance in their distribution. Relevant progress in CD, intestinal epithelial permeability, and DCs highlighting a potential relationship between increased epithelial permeability and abnormal DC distribution during the pathogenesis of intestinal inflammation.
Altered intestinal dendritic cell (DC) function underlies dysregulated T-cell responses to bacteria in Crohn’s disease (CD) but it is unclear whether composition of the intestinal microbiota impacts local DC function. The relationship between DC function with disease activity and intestinal microbiota in patients with CD. Surface expression of Toll-like receptor (TLR)-2, TLR-4, and spontaneous intracellular interleukin (IL)-10, IL-12p40, IL-6 production by freshly isolated DC were analyzed by multicolor flow cytometry of cells extracted from rectal tissue of 10 controls and 28 CD patients. Myeloid DC were identified as CD11c(+) HLA-DR(+lin-/dim) cells (lin = anti-CD3, CD14, CD16, CD19, CD34). Intestinal microbiota were analyzed by fluorescent in situ hybridization of fecal samples with oligonucleotide probes targeting 16S rRNA of bifidobacteria, bacteroides-prevotella, C. coccoides-E. rectale, and Faecalibacterium prausnitzii.
DC from CD produced higher amounts of IL-12p40 and IL-6 than control DC. IL-6(+) DC were associated with the CD Activity Index and serum C-reactive protein (CRP). DC expression of TLR-4 correlated with disease activity. IL-12p40(+) DC correlated with ratio of bacteroides: bifidobacteria. IL-10(+) DC correlated with bifidobacteria, and IL-6(+) DC correlated negatively with F. prausnitzii. The amount of TLR-4 on DC correlated negatively with the concentration of F. prausnitzii.
IL-6 production by intestinal DC is increased in CD and correlates with disease activity and CRP. Bacterially driven local IL-6 production by intestinal DC may overcome regulatory activity, resulting in unopposed effector function and tissue damage. Intestinal DC function may be influenced by the composition of the commensal microbiota.
Helicobacter pylori DNA decreases pro-inflammatory cytokine production by dendritic cells and colitis.
Epidemiological data have recently emerged to suggest Helicobacter pylori may protect against certain chronic inflammatory diseases such as inflammatory bowel disease (IBD). However, the mechanism for the observed inverse association between H pylori and IBD has not been described. The frequency of immunoregulatory (IRS) to immunostimulatory (ISS) sequences within the genome of various bacteria was calculated using MacVector software. The induction of type I IFN and IL-12 responses by DNA-pulsed murine bone marrow-derived dendritic cells (BMDC) and human plasmacytoid dendritic cells (DC) was analysed by cytokine production. The effect of H pylori DNA on Escherichia coli DNA production of type I IFN and IL-12 was assessed. The in-vivo significance of H pylori DNA suppression was assessed in a dextran sodium sulphate (DSS) model of colitis. The systemic levels of type I IFN were assessed in H pylori-colonised and non-colonised patients.
H pylori DNA has a significantly elevated IRS:ISS ratio. In-vitro experiments revealed the inability of H pylori DNA to stimulate type I IFN or IL-12 production from mouse BMDC or human plasmacytoid DC. H pylori DNA was also able to suppress E coli DNA production of type I IFN and IL-12. The administration of H pylori DNA before the induction of DSS colitis significantly ameliorated the severity of colitis compared with E coli DNA or vehicle control in both an acute and chronic model. Finally, the systemic levels of type I IFN were found to be lower in H pylori-colonised patients than non-colonised controls. H pylori DNA has the ability to downregulate pro-inflammatory responses from DC and this may partly explain the inverse association between H pylori and IBD.
Dendritic cells prevent rather than promote immunity conferred by a helicobacter vaccine
Immunization against the gastric bacterium Helicobacter pylori could prevent many gastric cancers and other disorders. Most vaccination protocols used in preclinical models are not suitable for humans. New adjuvants and a better understanding of the correlates and requirements for vaccine-induced protection are needed to accelerate development of vaccines for H pylori. Vaccine-induced protection against H pylori infection and its local and systemic immunological correlates were assessed in animal models, using cholera toxin or CAF01 as adjuvants. The contribution of B cells, T-helper (Th)-cell subsets, and dendritic cells to H pylori-specific protection were analyzed in mice.
Parenteral administration of a whole-cell sonicate, combined with the mycobacterial cell-wall-derived adjuvant CAF01, protected against infection with H pylori and required cell-mediated, but not humoral, immunity. The vaccine-induced control of H pylori was accompanied by Th1 and Th17 responses in the gastric mucosa and in the gut-draining mesenteric lymph nodes; both Th subsets were required for protective immunity against H pylori. The numbers of memory CD4+ T cells and neutrophils in gastric tissue were identified as the best correlates of protection. Systemic depletion of dendritic cells or regulatory T cells during challenge infection significantly increased protection by overriding immunological tolerance mechanisms activated by live H pylori.
Parenteral immunization with a Helicobacter vaccine using a novel mycobacterial adjuvant induces protective immunity against H pylori that is mediated by Th1 and Th17 cells. Tolerance mechanisms mediated by dendritic cells and regulatory T cells impair H pylori clearance and must be overcome to improve immunity.
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