Dendritic cells of the gastrointestinal tract

Conclusion The studies of PP, LP, mesenteric LN, and thoracic duct lymph DCs now allow us to propose a basic outline of DC function in the mucosal immune system. In the organized lymphoid follicles, such as the PP, DCs in the subepithelial dome acquire luminal antigens after transport of the latter by M cells. They then present antigens to CD4⁺ T cells in the subepithelial dome or B cell follicles or, following activation/maturation and migration to the interfollicular T cell regions, to both CD4⁺ and CD8⁺ T cells. Alternatively, the DCs migrate via afferent lymphatics to the mesenteric LNs where they prime T cells at this site. In the diffuse lymphoid area of the LP, DCs acquire antigen via cellular extensions that pierce the basement membrane, or by DCs present in the epithelium. DCs above or below the basement membrane could process antigens transported across the basolateral membranes by epithelial cells, or alternatively, could directly sample intestinal antigens by dendrites that reach the intestinal lumen. These DCs then present antigen to IELS within the epithelium, to T cells in the LP, or following migration, to T cells in mesenteric LNs. A major unanswered question concerning this distribution of professional antigen-presenting cells is whether presentation of antigen by different DC populations has different outcomes. In addition, it remains unclear whether DCs from non-mucosal locations migrate to mucosal sites, or whether DCs from mucosal sites migrate to systemic lymphoid organs beyond the mesenteric LNs. Many active studies of mucosal immunity are centered around these questions and we await their outcome.     

Regulation of mononuclear phagocyte function by the microbiota at mucosal sites

Mucosal tissues contain distinct microbial communities that differ drastically depending on the barrier site, and as such, mucosal immune responses have evolved to be tailored specifically for their location. Whether protective or regulatory immune responses against invading pathogens or the commensal microbiota occur is controlled by local mononuclear phagocytes (MNPs). Comprising macrophages and dendritic cells (DCs), the functions of these cells are highly dependent on the local environment. For example, the intestine contains the greatest bacterial load of any site in the body, and hence, intestinal MNPs are hyporesponsive to bacterial stimulation. This is thought to be one of the major mechanisms by which harmful immune responses directed against the trillions of harmless bacteria that line the gut lumen are avoided. Regulation of MNP function by the microbiota has been characterized in the most depth in the intestine but there are several mucosal sites that also contain their own microbiota. In this review, we present an overview of how MNP function is regulated by the microbiota at mucosal sites, highlighting recent novel pathways by which this occurs in the intestine, and new studies elucidating these interactions at mucosal sites that have been characterized in less depth, including the urogenital tract.     

Intestinal dendritic cells in the regulation of mucosal immunity

The intestine presents a huge surface area to the outside environment, a property that is of critical importance for its key functions in nutrient digestion, absorption, and waste disposal. As such, the intestine is constantly exposed to dietary and microbial-derived foreign antigens, to which immune cells within the mucosa must suitably respond to maintain intestinal integrity, while also providing the ability to mount effective immune responses to potential pathogens. Dendritic cells (DCs) are sentinel immune cells that play a central role in the initiation and differentiation of adaptive immune responses. In the intestinal mucosa, DCs are located diffusely throughout the intestinal lamina propria, within gut-associated lymphoid tissues, including Peyer's patches and smaller lymphoid aggregates, as well as in intestinal-draining lymph nodes, including mesenteric lymph nodes. The recognition that dietary nutrients and microbial communities in the intestine influence both mucosal and systemic immune cell development and function as well as immune-mediated disease has led to an explosion of literature in mucosal immunology in recent years and a growing interest in the functionality of intestinal DCs. In the current review, we discuss recent findings from our group and others that have provided important insights regarding murine and human intestinal lamina propria DCs and highlighted marked developmental and functional heterogeneity within this compartment. A thorough understanding of the role these subsets play in the regulation of intestinal immune homeostasis and inflammation will help to define novel strategies for the treatment of intestinal pathologies and contribute to improved rational design of mucosal vaccines.     

The interaction of HIV with dendritic cells: outcomes and pathways

Dendritic cells (DCs), including Langerhans Cells (LCs), are probably among the earliest targets of HIV infection. Their localization in mucosal epithelia and in the T cell areas of lymphoid organs, as well as their crucial role in capturing antigens and initiating T cell responses, highlight their potential importance. Studies with cells in culture have addressed different outcomes of the HIV--DC interaction, which include: direct productive infection of DC; carriage of virus by DC to CD4+ T cells; transfer of virus between DC and T cells at an infectious synapse; and immune evasion strategies of infected DC. Here we review the literature covering these areas, including current knowledge of underlying mechanisms or pathways.     

Peyer's patches: organizing B-cell responses at the intestinal frontier

Secondary lymphoid tissues share the important function of bringing together antigens and rare antigen-specific lymphocytes to foster induction of adaptive immune responses. Peyer's patches (PPs) are unique compared to other secondary lymphoid tissues in their continual exposure to an enormous diversity of microbiome- and food-derived antigens and in the types of pathogens they encounter. Antigens are delivered to PPs by specialized microfold (M) epithelial cells and they may be captured and presented by resident dendritic cells (DCs). In accord with their state of chronic microbial antigen exposure, PPs exhibit continual germinal center (GC) activity. These GCs not only contribute to the generation of B cells and plasma cells producing somatically mutated gut antigen-specific IgA antibodies but have also been suggested to support non-specific antigen diversification of the B-cell repertoire. Here, we review current understanding of how PPs foster B-cell encounters with antigen, how they favor isotype switching to the secretory IgA isotype, and how their GC responses may uniquely contribute to mucosal immunity.     

Immunological and Regulatory Functions of Uninfected and Virus Infected Immature and Mature Subtypes of Dendritic Cells – a Review

In 1868, dendritic cells (DCs) were discovered in human skin by Paul Langerhans using gold staining. These cells were named Langerhans cells (LCs) after their discoverer who, due to their dendrites, regarded them as neurons. One hundred and eleven years were to pass until it was discovered that in vertebrates these cells originate in the bone marrow as monocytes. In the 1980s, DC research was mostly carried out on DCs that are present in different tissues of mice and humans. These studies revealed that after interaction with foreign antigens, skin LCs/DCs migrate through the lymph vessels to the draining lymph nodes and induce the two arms of the immune response. The isolation of DCs from tissue cell suspensions opened the way to studies on the cells' surface proteins and their ability to stimulate immune responses. During the 1990s, studies revealed the role of DCs in the activation of naïve T cells in the lymph nodes and the regulatory properties of DCs in lymph nodes, thymus, gut, and spleen.Part A of the review deals with the DC system of human and mice and immunological and regulatory functions of subsets of DCs in the skin with reference to migrating and stationary DCs, as well as the connection between DCs and the nervous system. Furthermore, the origin of both follicular DCs that are present in lymphoid tissues and thymic DCs are discussed. Part B is devoted to virus infections of DCs with an emphasis on infections caused by human herpes viruses. Part C presents the modulation of DC gene expression in response to the influenza virus. Contemporary research focuses on the role of DCs in the immune systems of vertebrates. Moreover, studies are being conducted on the regulatory functions of DCs by tissue cells in different organs of vertebrates.     

Improving M cell mediated transport across mucosal barriers: do certain bacteria hold the keys?

Specialized microfold (M) cells of the follicle-associated epithelium (FAE) of the mucosal-associated lymphoid tissue (MALT) in gut and the respiratory system play an important role in the genesis of both mucosal and systemic immune responses by delivering antigenic substrate to the underlying lymphoid tissue where immune responses start. Although it has been shown that dendritic cells (DC) also have the ability to sample antigens directly from the gut lumen, M cells certainly remain the most important antigen-sampling cell to be investigated in order to devise novel methods to improve mucosal delivery of biologically active compounds. Recently, novel information on the interactions between bacteria and FAE have come to light that unveil further the complex cross-talk taking place at mucosal interfaces between bacteria, epithelial cells and the immune system and which are central to the formation and function of M cells. In particular, it has been shown that M cell mediated transport of antigen across the FAE is improved rapidly by exposure to certain bacteria, thus opening the way to identify new means to achieve a more effective mucosal delivery. Here, these novel findings and their potential in mucosal immunity are analysed and discussed, and new approaches to improve antigen delivery to the mucosal immune system are also proposed.     

Harnessing dendritic cells for immunotherapy

Dendritic cells (DC) are the antigen presenting cells that initiate and direct adaptive immune responses, capable of inducing protective adaptive immune responses and tolerance. They sample their surroundings, internalizing, processing and presenting antigens to T cells. They distinguish between self and foreign antigens with a wide array of microbial sensors, and induce immunity when antigen is captured in the presence of microbial products or inflammatory stimuli, but tolerance in the absence of these signals. However, not all DCs are identical. There are distinct DC subsets spread throughout the body, and although they share common features, they also have specialized functions. As a consequence, the outcome of the immune response is determined by the context in which the antigen is acquired, and also by the DC subset(s) involved. Here we discuss the features of the DC subsets, their handling of antigens for MHCI- and MHCII-restricted presentation, how their functions are regulated by foreign and endogenous signals, the consequences on the type of immune response induced, and how they provide insights on the design of immunotherapy.     

Butyrate and retinoic acid imprint mucosal‐like dendritic cell development synergistically from bone marrow cells

Accumulating data show that the phenotypes and functions of distinctive mucosal dendritic cells (DCs) in the gut are regulated by retinoic acid (RA). Unfortunately, the exact role of butyrate in RA‐mediated mucosal DC differentiation has not been elucidated thoroughly to date. Mucosal‐like dendritic cell differentiation was completed in vitro by culturing bone marrow cells with growth factors [granulocyte–macrophage colony‐stimulating factor (GM‐CSF/interleukin (IL)‐4], RA and/or butyrate. The phenotypes, cytokine secretion, immune functions and levels of retinal dehydrogenase of different DCs were detected using quantitative polymerase chain reaction (qPCR), enzyme‐linked immunosorbent assay (ELISA) and flow cytometry, respectively. The results showed that RA‐induced DCs (RA‐DCs) showed mucosal DC properties, including expression of CD103 and gut homing receptor α₄β₇, low proinflammatory cytokine secretion and low priming capability to antigen‐specific CD4⁺ T cells. Butyrate‐treated RA‐DCs (Bu‐RA‐DCs) decreased CD11c, but increased CD103 and α₄β₇ expression. Moreover, the CD4⁺ T priming capability and the levels of retinal dehydrogenase of RA‐DCs were suppressed significantly by butyrate. Thus, butyrate and retinoic acid have different but synergistic regulatory functions on mucosal DC differentiation, indicating that immune homeostasis in the gut depends largely upon RA and butyrate to imprint different mucosal DC subsets, both individually and collectively.     

How the interplay between antigen presenting cells and microbiota tunes host immune responses in the gut

Coordination of immune responses in the gut is a complex task. In order to fight pathogens and maintain a defined population of commensal microbes, the mucosal immune system has to coordinate information from the external (luminal) and internal (abluminal) environment and respond accordingly. Dendritic cells (DCs) are crucial cell types involved in this process as they integrate these signals and direct immunogenic or tolerogenic responses. Here, we review how various functions of DCs depend on microbial stimuli and how these stimuli influence the course of immune activation.     

Redox Control of Indoleamine 2,3‐Dioxygenase Expression and Activity in Human Monocyte‐Derived Dendritic Cells is Independent of Changes in Oxygen Tension

Dendritic cells (DCs) initiate adaptive immune responses to pathogens and tumours and maintain tolerance to self and innocuous antigens. These functions occur in organs and tissues exhibiting wide variations in nutrients, growth factors, redox and oxygen tension. Understanding how these microenvironmental factors influence DCs to affect immunological outcomes is of increasing relevance with the emerging success of DC‐based cellular vaccines. In a previous study, we examined whether redox, an important environmental cue, could influence DC expression of the immunosuppressive enzyme indoleamine 2,3‐dioxygenase (IDO). IDO‐competent DCs promote long‐term immune homoeostasis by limiting exaggerated inflammatory responses and directing regulatory T‐cell effector function. To alter redox, we manipulated the activity of the cystine/glutamate antiporter, which functions to maintain intracellular and extracellular redox. The results of that study showed that redox perturbation strongly induced IDO expression and activity in DCs. While this study was performed using standard cell culture techniques with DCs cultured under 5% CO₂ and 20% O₂, it is clear that DCs capture and present antigens in inflamed tissues and secondary lymphoid organs which exhibit low oxygen tension (1–5% O₂). Therefore, here we investigated whether oxygen tension influences DC expression of IDO in the context of homoeostatic and altered redox.     

How vitamin A metabolizing dendritic cells are generated in the gut mucosa

CD103(+) dendritic cells (DCs) represent the major migratory DC population in the intestinal lamina propria and are believed to play an essential role in the initiation and regulation of mucosal adaptive immune responses. Small intestine (SI) CD103(+) DCs have an enhanced capacity to generate the vitamin A metabolite, retinoic acid, a property that underlies their ability to induce the gut homing receptors CC chemokine receptor 9 and α4β7 on responding T and B cells, and enhance forkhead box P3(+) T regulatory and IgA plasma cell differentiation in vitro. In this review, we discuss the environmental signals that appear to promote vitamin A metabolising activity in SI CD103(+) DCs in the steady state and thus which may contribute to driving the unique nature of SI immune responses.     

The development and function of mucosal lymphoid tissues: a balancing act with micro-organisms

Mucosal surfaces are constantly exposed to environmental antigens, colonized by commensal organisms and used by pathogens as points of entry. As a result, the immune system has devoted the bulk of its resources to mucosal sites to maintain symbiosis with commensal organisms, prevent pathogen entry, and avoid unnecessary inflammatory responses to innocuous antigens. These functions are facilitated by a variety of mucosal lymphoid organs that develop during embryogenesis in the absence of microbial stimulation as well as ectopic lymphoid tissues that develop in adults following microbial exposure or inflammation. Each of these lymphoid organs samples antigens from different mucosal sites and contributes to immune homeostasis, commensal containment, and immunity to pathogens. Here we discuss the mechanisms, mostly based on mouse studies, that control the development of mucosal lymphoid organs and how the various lymphoid tissues cooperate to maintain the integrity of the mucosal barrier.     

Host–microbiota interactions within the fish intestinal ecosystem

Teleost fish are in direct contact with the aquatic environment, and are therefore in continual contact with a complex and dynamic microbiota, some of which may have implications for health. Mucosal surfaces represent the main sites in which environmental antigens and intestinal microbiota interact with the host. Thus, the gut-associated lymphoid tissues (GALT) must develop mechanisms to discriminate between pathogenic and commensal microorganisms. Colonization of intestinal mucosal surfaces with a normal microbiota has a positive effect on immune regulatory functions of the gut, and disturbance in these immune regulatory functions by an imbalanced microbiota may contribute to the development of diseases. Significant attention has therefore been recently focused on the role of probiotics in the induction or restoration of a disturbed microbiota to its normal beneficial composition. Given this, this article explores the fascinating relationship between the fish immune system and the bacteria that are present in its intestinal microbiota, focusing on the bacterial effect on the development of certain immune responses.     

The microbiome and regulation of mucosal immunity

The gastrointestinal tract is a mucosal surface constantly exposed to foreign antigens and microbes, and is protected by a vast array of immunologically active structures and cells. Epithelial cells directly participate in immunological surveillance and direction of host responses in the gut and can express numerous pattern recognition receptors, including Toll‐like receptor 5 (TLR5), TLR1, TLR2, TLR3, TLR9, and nucleotide oligomerization domain 2, as well as produce chemotactic factors for both myeloid and lymphoid cells following inflammatory stimulation. Within the epithelium and in the underlying lamina propria resides a population of innate lymphoid cells that, following stimulation, can become activated and produce effector cytokines and exert both protective and pathogenic roles during inflammation. Lamina propria dendritic cells play a large role in determining whether the response to a particular antigen will be inflammatory or anti‐inflammatory. It is becoming clear that the composition and metabolic activity of the intestinal microbiome, as a whole community, exerts a profound influence on mucosal immune regulation. The microbiome produces short‐chain fatty acids, polysaccharide A, α‐galactosylceramide and tryptophan metabolites, which can induce interleukin‐22, Reg3γ, IgA and interleukin‐17 responses. However, much of what is known about microbiome–host immune interactions has come from the study of single bacterial members of the gastrointestinal microbiome and their impact on intestinal mucosal immunity. Additionally, evidence continues to accumulate that alterations of the intestinal microbiome can impact not only gastrointestinal immunity but also immune regulation at distal mucosal sites.     

Function of Mucosa-Associated Lymphoid Tissue in Antibody Formation

Abundant evidence supports the notion that human intestinal plasma cells are largely derived from B cells initially activated in gut-associated lymphoid tissue (GALT). Nevertheless, insufficient knowledge exists about the uptake, processing, and presentation of luminal antigens occurring in GALT to accomplish priming and sustained expansion of mucosal B cells. Also, it is unclear how the germinal center reaction so strikingly promotes class switch to IgA and expression of J chain, although the commensal microbiota appears to contribute to both diversification and memory. B-cell migration from GALT to the intestinal lamina propria is guided by rather well-defined adhesion molecules and chemokines/chemokine receptors, but the cues directing homing to secretory effector sites beyond the gut require better definition. In this respect, the role of human Waldeyer's ring (including adenoids and the palatine tonsils) as a regional mucosa-associated lymphoid tissue must be better defined, although the balance of evidence suggests that it functions as nasopharynx-associated lymphoid tissue (NALT) like the characteristic NALT structures in rodents. Altogether, data suggest a remarkable compartmentalization of the mucosal immune system that must be taken into account in the development of effective local vaccines to protect specifically the airways, small and large intestines, and the female genital tract.     

Tolerogenic dendritic cells and their potential applications

Dendritic cells (DCs) play a pivotal role in regulating the balance between immunity and tolerance of the immune system. Recent advancements in DC biology and techniques for manipulating the function of these cells have shown their immense therapeutic potential for treating a variety of immune disorders. Theoretically, antigen-specific tolerogenic DCs can be generated in vitro and delivered to patients to correct the dysfunctional immune responses that attack their own tissues or over-react to innocuous foreign antigens. However, DCs are a heterogeneous population of cells with differences in cell surface makers, differentiation pathways and functions. Studies are needed to examine which subset of DCs can be used for what type of applications. Furthermore, most of the information on tolerogenic DCs has been obtained from animal models and translational studies are needed to examine how a DC therapeutic strategy can be implemented clinically to modulate immunity.     

Mucosal T cells in gut homeostasis and inflammation

The antigen-rich environment of the gut interacts with a highly integrated and specialized mucosal immune system that has the challenging task of preventing invasion and the systemic spread of microbes, while avoiding excessive or unnecessary immune responses to innocuous antigens. Disruption of the mucosal barrier and/or defects in gut immune regulatory networks may lead to chronic intestinal inflammation as seen in inflammatory bowel disease. The T-cell populations of the intestine play a critical role in controlling intestinal homeostasis, and their unique phenotypes and diversities reflect the sophisticated mechanisms that have evolved to maintain the delicate balance between immune activation and tolerance at mucosal sites. In this article, we will discuss the specialized properties of mucosal T cells in the context of immune homeostasis and inflammation.     

How dendritic cells and microbes interact to elicit or subvert protective immune responses

B and T lymphocytes recognize antigens with high specificity, but neither initiate immune responses, nor decide their types. These functions rest upon dendritic cells (DCs), which can determine and maintain Th1/Th2 polarization. Immune responses are thus dependent on the DC subset, the receptors that recognize each pathogen and the microenvironment. Microbes employ an array of mechanisms to evade and disrupt DC functions; some even hijack DCs for transport around the body. Our progress in the understanding of DC physiology will hopefully help us create the necessary vaccines to counteract the infectious agents that still plague mankind.     

Involvement of intestinal dendritic cells in oral tolerance, immunity to pathogens, and inflammatory bowel disease

Summary: Dendritic cells (DCs) are composed of a family of cells, now recognized to be essential for innate and acquired immunity. DCs at mucosal surfaces have a particular capacity to induce the differentiation of regulatory T cells producing interleukin‐10 (IL‐10) and transforming growth factor‐β (TGF‐β) in the steady state (non‐infected, non‐immunized), yet they retain the capacity to induce effector T cells in response to invasive pathogens. This decision between the induction of active immunity and tolerance will depend on the subpopulation of DC involved and the surface receptors engaged during DC activation and T‐cell priming. The local microenvironment will likely play an important role both in defining the DC phenotype and in providing direct signals to responding T cells. Furthermore, DCs in organized mucosal lymphoid tissues preferentially induce the expression of CCR9 and α4β7 on T cells, which results in T‐cell homing to the intestinal lamina propria. Finally, DCs may play an important role in the maintenance of abnormal intestinal inflammation either by driving pathogenic T‐cell responses in mesenteric lymph nodes or by acting to expand or maintain pathogenic T cells locally at sites of inflammation. In this review, a brief discussion of general issues of DC biology that are pertinent to mucosal immunity is followed by a more in‐depth discussion of the phenotype and function of DC populations in the intestine.