Function Of Intestinal Dendritic Cells Research Articles

Dietary protein modulates intestinal dendritic cells to establish mucosal homeostasis

Dietary proteins are taken up by intestinal dendritic cells (DC), cleaved into peptides, loaded to Major Histocompatibility Compexes (MHC), and presented to T cells to generate an immune response. Amino acid (AA)-diets do not have the same effects because AAs cannot bind to MHC to activate T cells. Here, we show that impairment in Treg cell generation and loss of tolerance in mice fed a diet lacking whole protein is associated with major transcriptional changes in intestinal DCs including downregulation of genes related to DC maturation, activation and migration and decreased gene expression of immune checkpoint molecules. Moreover, the AA-diet had a profound effect on microbiome composition, including an increase in Akkermansia muciniphilia and Oscillibacter and decrease in Lactococcus lactis and Bifidobacterium. Although microbiome transfer experiments showed that AA driven microbiome modulate intestinal DC gene expression, most of the unique transcriptional change in DC was linked to the absence of whole protein in the diet. Our findings highlight the importance of dietary proteins for intestinal DC function and mucosal tolerance.

Regulation of IgA Production by Intestinal Dendritic Cells and Related Cells.

The intestinal mucosa is a physiological barrier for most microbes, including both commensal bacteria and invading pathogens. Under homeostatic conditions, immunoglobulin A (IgA) is the major immunoglobulin isotype in the intestinal mucosa. Microbes stimulate the production of IgA, which controls bacterial translocation and neutralizes bacterial toxins at the intestinal mucosal surface. In the intestinal mucosa, dendritic cells (DCs), specialized antigen-presenting cells, regulate both T-cell-dependent (TD) and -independent (TI) immune responses. The intestinal DCs are a heterogeneous population that includes unique subsets that induce IgA synthesis in B cells. The characteristics of intestinal DCs are strongly influenced by the microenvironment, including the presence of commensal bacterial metabolites and epithelial cell-derived soluble factors. In this review, we summarize the ontogeny, classification, and function of intestinal DCs and how the intestinal microenvironment conditions DCs and their precursors to become the mucosal phenotype, in particular to regulate IgA production, after they arrive at the intestine. Understanding the mechanism of IgA synthesis could provide insights for designing effective mucosal vaccines.

Intestinal dendritic cell licensing through Toll-like receptor 4 is required for oral tolerance in allergic contact dermatitis

Induction of oral tolerance to haptens is an efficient way to prevent allergic contact dermatitis (ACD) in mice. Toll-like receptor (TLR)-mediated sensing of the microbiota contributes to gut homeostasis, yet whether it contributes to induction of oral tolerance has not been documented. We examined whether oral tolerance to the contact sensitizer 2,4-dinitro-fluorobenzene (DNFB) depends on microbiota/TLRs and evaluated the role of TLR4 on the tolerogenic function of intestinal dendritic cells (DCs). Oral tolerance was induced by DNFB gavage in germ-free and mice deficient in several TLRs. Tolerance was assessed by means of suppression of contact hypersensitivity and hapten-specific IFN-γ-producing effector T cells. The tolerogenic function of intestinal DCs was tested by adoptive transfer experiments, exvivo hapten presentation, and forkhead box p3 regulatory T-cell conversion. Oral tolerance induced by DNFB gavage was impaired in germ-free mice and TLR4-deficient mice. Bone marrow chimeras revealed that TLR4 expression on hematopoietic cells was necessary for oral tolerance induction. TLR4 appeared to be essential for the ability of intestinal dendritic cells from DNFB-fed mice to inhibit ACD on adoptive transfer. Indeed, TLR4 conditioned the invivo mobilization to mesenteric lymph nodes of intestinal migratory CD103+ DCs carrying oral DNFB, especially the CD103+CD11b+ DC subset expressing the vitamin A-converting enzyme retinaldehyde dehydrogenase and specialized in forkhead box p3-positive regulatory T-cell conversion. Our data demonstrate that TLR4 conditions induction of oral tolerance to DNFB through licensing tolerogenic gut DCs. Oral biotherapy with TLR4 ligands might be useful to potentiate oral tolerance to haptens and alleviate ACD in human subjects.

MicroRNA-223 Regulates the Differentiation and Function of Intestinal Dendritic Cells and Macrophages by Targeting C/EBPβ.

Dendritic cells (DCs) and macrophages play important roles in maintaining intestinal homeostasis. However, the molecular mechanisms that regulate the differentiation and responses of intestinal DCs and macrophages remain poorly understood. Here, we have identified microRNA miR-223 as a key molecule for regulating these processes. Deficiency of miR-223 led to a significantly decreased number of intestinal CX3CR1(hi) macrophages at steady state. Both intestinal CX3CR1(hi) macrophages and CD103(+) conventional DCs (cDCs) in miR-223-deficient mice exhibited a strong pro-inflammatory phenotype. Moreover, miR-223-deficient monocytes gave rise to more monocyte-derived DCs (moDCs) and produced more pro-inflammatory cytokines upon stimulation. Using a mouse model of colitis, we demonstrated that the miR-223 deficiency resulted in more severe colitis. Target gene analysis further identified that the effects of miR-223 on DCs and macrophages were mediated by directly targeting C/EBPβ. Taken together, our study identifies a role for miR-223 as a critical regulator of intestinal homeostasis.

Corticotropin-releasing Factor Changes the Phenotype and Function of Dendritic Cells in Mouse Mesenteric Lymph Nodes.

Background/AimsDendritic cells (DCs) are a significant contributor to the pathology of numerous chronic inflammatory autoimmune disorders; however, the effects of Corticotropin-releasing factor (CRF) on intestinal DCs are poorly understood. In this study, we investigated the role of CRF in alterations of intestinal dendritic cell phenotype and function.MethodsMouse mesenteric lymph node dendritic cells (MLNDCs) were obtained using magnetic bead sorting. Surface expression of CRF receptor type 1 (CRF-R1) and CRF-R2 was determined by double-labeling immunofluorescence and quantitative polymerase chain reaction (qPCR) and MLNDCs were subsequently exposed to CRF in the presence or absence of CRF-R1 and CRF-R2 antagonists. Expression of surface molecules (MHC-I and MHC-II) and co-stimulatory molecules (CD80 and CD86) was determined by flow cytometric and western blot analyses, and the T cell stimulatory capacity of MLNDCs was evaluated by mixed lymphocyte reaction.ResultsImmunofluorescent staining and quatitative polymerase chain reaction indicated that both the CRF receptors (CRF-R1 and CRF-2) are expressed on the surface of MLNDCs. Exposure to CRF increased the expression of MHC-II on MLNDCs as well as their capacity to stimulate T cell proliferation. MLNDCs treated with CRF-R1 antagonist exhibited a phenotype characterized by a less activated state and reduced surface expression of MHC-II, and consequently showed reduced capacity to stimulate T cells. In contrast, treatment of MLNDCs with CRF-R2 antagonist yielded an opposite result.ConclusionsCRF can alter the phenotype and function of intestinal DCs through direct action on CRF-R1 and CRF-R2, and activation of the CRF-R1 and CRF-R2 pathways yields opposing outcomes.

Regulation of intestinal immune system by dendritic cells.

Innate immune cells survey antigenic materials beneath our body surfaces and provide a front-line response to internal and external danger signals. Dendritic cells (DCs), a subset of innate immune cells, are critical sentinels that perform multiple roles in immune responses, from acting as principal modulators to priming an adaptive immune response through antigen-specific signaling. In the gut, DCs meet exogenous, non-harmful food antigens as well as vast commensal microbes under steady-state conditions. In other instances, they must combat pathogenic microbes to prevent infections. In this review, we focus on the function of intestinal DCs in maintaining intestinal immune homeostasis. Specifically, we describe how intestinal DCs affect IgA production from B cells and influence the generation of unique subsets of T cell.

Homeobox Transcription Factor VentX Regulates Differentiation and Maturation of Human Dendritic Cells

Dendritic cells (DCs) are specialized antigen presentation cells that play critical roles in the initiation and regulation of immune responses. The molecular determinants of DC differentiation and maturation are target of extensive investigation. VentX is a human homeobox transcriptional factor that regulates proliferation and differentiation of hematopoietic cells. In the current study, we report that ablation of VentX expression in monocytes significantly impaired their differentiation into DCs. Conversely, overexpression of VentX in monocytic THP1 cells accelerated their differentiation toward DCs. We showed that VentX regulates DC differentiation, in part, through modulating IL6 expression. Clinically, we found that VentX expression was elevated in intestinal lamina propria DCs (LPDCs) of inflamed mucosa from inflammatory bowel disease patients. Knockdown experiments suggested that VentX is essential for the maturation of LPDCs. In addition, corticosteroid treatment markedly decreased VentX expression in LPDCs and enforced expression of VentX counteracted the effects of corticosteroid on DCs maturation. Our data suggest that VentX is a critical transcriptional regulator of DC differentiation and maturation, and a potential target of immune regulation and therapy.

Induction of ALDH Activity in Intestinal Dendritic Cells byLactobacillus plantarumNRIC0380

Lactic acid bacteria have been reported to have various immune-regulating activities. We also found in the previous study that the oral administration of heat-killed Lactobacillus plantarum NRIC0380 induced CD4(+)CD25(+)Foxp3(+) cells (Treg cells). We examine in this present study the influence of NRIC0380 on the function of intestinal dendritic cells (DCs) in vitro and in vivo. The aldehyde dehydrogenase (ALDH) activity was significantly induced in DCs obtained from the mesenteric lymph node (MLN) by culturing with NRIC0380. The oral administration of NRIC0380 also significantly increased ALDH-positive DCs in MLN. NRIC0380 significantly enhanced the production of TGF-β from MLN cells in vitro. These effects were not apparent in cells from the Peyer's patch (PP) and spleen (SPL). NRIC0380 also significantly enhanced the expression of B7-H1 on DCs of all organs in vitro. The effects of NRIC0380 on DCs, especially those located in MLN, might be involved in its function to induce Treg cells.

Immunosuppressive effects via human intestinal dendritic cells of probiotic bacteria and steroids in the treatment of acute ulcerative colitis

In ulcerative colitis (UC) gut bacteria drive inflammation. Bacterial recognition and T-cell responses are shaped by intestinal dendritic cells (DCs); therapeutic effects of probiotic bacteria may relate to modulation of intestinal DC. The probiotic mixture, VSL#3, increases interleukin (IL)-10 and downregulates IL-12p40 production by DC in vitro. We evaluated in vivo effects of oral VSL#3 and steroids on colonic DC in patients with acute UC. Rectal biopsies were obtained from patients with active UC before and after treatment with VSL#3, corticosteroids, or placebo, and from healthy controls. Myeloid colonic DC were studied from freshly isolated lamina propria cells using multicolor flow cytometry. Surface expression of activation markers, CD40, CD86, pattern recognition receptors, Toll-like receptor (TLR)-2 and TLR-4 were assessed. Changed function was measured from ongoing intracellular IL-10, IL-12p40, IL-6, and IL-13 production. Acute UC colonic myeloid DC were producing more IL-10 and IL-12p40 than control DC (P = 0.01). In VSL#3-treated patients DC TLR-2 expression decreased (P < 0.05), IL-10 production increased and IL-12p40 production decreased (P < 0.005); 10/14 patients on VSL#3 showed a clinical response. Corticosteroids also resulted in increased IL-10 and reduced IL-12p40 production by DC. Conversely, in patients on placebo, TLR-2 expression and intensity of staining for IL-12p40 and IL-6 increased (all P < 0.05); 5/14 patients on placebo showed a clinical response (P = NS). Despite small numbers of human colonic DC available, we showed that treatment of UC patients with probiotic VSL#3 and corticosteroids induced "favorable" intestinal DC function in vivo, increasing regulatory cytokines and lowering proinflammatory cytokines and TLR expression. These effects may contribute to therapeutic benefit.

Differential modulation in the functions of intestinal dendritic cells by long- and medium-chain fatty acids

Although dendritic cells (DCs) play significant roles in intestinal immune responses, little is known regarding the direct effects of luminal foods on DC functions in the intestinal mucosa. In this study, we examined the effects of fatty acids (FAs) with various chain length on the phagocytic function, antigen presentation, and chemotaxis of intestinal DCs. DCs obtained from the thoracic duct lymph of mesenteric lymphadenectomized rats were cultured with long [arachidonic acid (AA) or oleic acid] or medium (octanoic acid) chain FAs with interleukin-4 and granulocyte macrophage-colony stimulating factor. Tumor necrosis factor-alpha was added in the maturation group. Phagocytic function was examined by the intake of fluorescent microbeads. The expression of cell surface molecules was determined by immunocytochemistry or fluorescence-activated cell sorting (FACS). Antigen presentation ability was evaluated by coincubating keyhole limpet hemocyanin (KLH)-sensitized spleen lymphocytes and KLH-pulsed DCs. Migratory ability of DCs toward the chemokines CC chemokine ligand (CCL) 20 and CCL21 was also assessed. There was a maturation-induced decrease in phagocytic function, and an increased expression of major histocompatibility complex (MHC) class II molecules. Exposure of DCs to both long- and medium-chain FAs maintained phagocytic ability. The expression of MHC class II molecules was significantly suppressed only by long-chain FAs. The expression of costimulatory factors was suppressed only by AA. Long- but not medium-chain FAs suppressed the antigen presentation ability of DCs induced by maturation. Chemotactic ability of mature DCs toward CCL21 was abrogated only by long-chain FAs. The data suggest that intraluminal exposure to long- and medium-chain FAs may differentially modulate the immune functions of intestinal DCs.