Modulation Of Dendritic Cell Function Research Articles

SARS-CoV-2 suppresses TLR4-induced immunity by dendritic cells via C-type lectin receptor DC-SIGN.

SARS-CoV-2 causes COVID-19, an infectious disease with symptoms ranging from a mild cold to severe pneumonia, inflammation, and even death. Although strong inflammatory responses are a major factor in causing morbidity and mortality, superinfections with bacteria during severe COVID-19 often cause pneumonia, bacteremia and sepsis. Aberrant immune responses might underlie increased sensitivity to bacteria during COVID-19 but the mechanisms remain unclear. Here we investigated whether SARS-CoV-2 directly suppresses immune responses to bacteria. We studied the functionality of human dendritic cells (DCs) towards a variety of bacterial triggers after exposure to SARS-CoV-2 Spike (S) protein and SARS-CoV-2 primary isolate (hCoV-19/Italy). Notably, pre-exposure of DCs to either SARS-CoV-2 S protein or a SARS-CoV-2 isolate led to reduced type I interferon (IFN) and cytokine responses in response to Toll-like receptor (TLR)4 agonist lipopolysaccharide (LPS), whereas other TLR agonists were not affected. SARS-CoV-2 S protein interacted with the C-type lectin receptor DC-SIGN and, notably, blocking DC-SIGN with antibodies restored type I IFN and cytokine responses to LPS. Moreover, blocking the kinase Raf-1 by a small molecule inhibitor restored immune responses to LPS. These results suggest that SARS-CoV-2 modulates DC function upon TLR4 triggering via DC-SIGN-induced Raf-1 pathway. These data imply that SARS-CoV-2 actively suppresses DC function via DC-SIGN, which might account for the higher mortality rates observed in patients with COVID-19 and bacterial superinfections.

Dendritic cells in liver transplantation immune response.

Dendritic cells (DCs) are the most powerful antigen presenting cells (APCs), they are considered one of the key regulatory factors in the liver immune system. There is currently much interest in modulating DC function to improve transplant immune response. In liver transplantation, DCs participate in both the promotion and inhibition of the alloreponse by adopting different phenotypes and function. Thus, in this review, we discussed the origin, maturation, migration and pathological effects of several DC subsets, including the conventional DC (cDC), plasmacytoid DC (pDC) and monocyte-derived DC (Mo-DC) in liver transplantation, and we summarized the roles of these DC subsets in liver transplant rejection and tolerance. In addition, we also outlined the latest progress in DC-based related treatment regimens. Overall, our discussion provides a beneficial resource for better understanding the biology of DCs and their manipulation to improve the immune adaptability of patients in transplant status.

1,25(OH)2D3 Differently Modulates the Secretory Activity of IFN-DC and IL4-DC: A Study in Cells from Healthy Donors and MS Patients

Immune mechanisms play an essential role in driving multiple sclerosis (MS) and altered trafficking and/or activation of dendritic cells (DC) were observed in the central nervous system and cerebrospinal fluid of MS patients. Interferon β (IFNβ) has been used as a first-line therapy in MS for almost three decades and vitamin D deficiency is a recognized environmental risk factor for MS. Both IFNβ and vitamin D modulate DC functions. Here, we studied the response to 1,25-dihydoxyvitamin D3 (1,25(OH)2D3) of DC obtained with IFNβ/GM-CSF (IFN-DC) compared to classically derived IL4-DC, in three donor groups: MS patients free of therapy, MS patients undergoing IFNβ therapy, and healthy donors. Except for a decreased CCL2 secretion by IL4-DC from the MS group, no major defects were observed in the 1,25(OH)2D3 response of either IFN-DC or IL4-DC from MS donors compared to healthy donors. However, the two cell models strongly differed for vitamin D receptor level of expression as well as for basal and 1,25(OH)2D3-induced cytokine/chemokine secretion. 1,25(OH)2D3 up-modulated IL6, its soluble receptor sIL6R, and CCL5 in IL4-DC, and down-modulated IL10 in IFN-DC. IFN-DC, but not IL4-DC, constitutively secreted high levels of IL8 and of matrix-metalloproteinase-9, both down-modulated by 1,25(OH)2D3. DC may contribute to MS pathogenesis, but also provide an avenue for therapeutic intervention. 1,25(OH)2D3-induced tolerogenic DC are in clinical trial for MS. We show that the protocol of in vitro DC differentiation qualitatively and quantitatively affects secretion of cytokines and chemokines deeply involved in MS pathogenesis.

Engineering Hydrogels for Modulation of Dendritic Cell Function.

Dendritic cells (DCs), the most potent antigen-presenting cells, are necessary for the effective activation of naïve T cells. DCs encounter numerous microenvironments with different biophysical properties, such as stiffness and viscoelasticity. Considering the emerging importance of mechanical cues for DC function, it is essential to understand the impacts of these cues on DC function in a physiological or pathological context. Engineered hydrogels have gained interest for the exploration of the impacts of biophysical matrix cues on DC functions, owing to their extracellular-matrix-mimetic properties, such as high water content, a sponge-like pore structure, and tunable mechanical properties. In this review, the introduction of gelation mechanisms of hydrogels is first summarized. Then, recent advances in the substantial effects of developing hydrogels on DC function are highlighted, and the potential molecular mechanisms are subsequently discussed. Finally, persisting questions and future perspectives are presented.

Semisynthetic Abietic and Dehydroabietic Acid Derivatives and Triptoquinone Epimers Interfere with LPS-Triggered Activation of Dendritic Cells.

Abietic acid (AA), dehydroabietic acid (DHA) and triptoquinones (TQs) are bioactive abietane-type diterpenoids, which are present in many edible vegetables and medicinal herbs with health-promoting properties. Evidence suggests that beneficial effects of diterpenes operate, at least in part, through effects on cells in the immune system. Dendritic cells (DCs) are a key type of leukocyte involved in the initiation and regulation of the immune/inflammatory response and natural or synthetic compounds that modulate DC functions could be potential anti-inflammatory/immunomodulatory agents. Herein, we report the screening of 23 known semisynthetic AA and DHA derivatives, and TQs, synthesized previously by us, in a multi-analyte DC-based assay that detects inhibition of pro-inflammatory cytokine production. Based on the magnitude of the inhibitory effect observed and the number of cytokines inhibited, a variety of activities among compounds were observed, ranging from inactive/weak to very potent inhibitors. Structurally, either alcohol or methyl ester substituents on ring A along with the introduction of aromaticity and oxidation in ring C in the abietane skeleton were found in compounds with higher inhibitory properties. Two DHA derivatives and two TQs exhibited a significant inhibition in all pro-inflammatory cytokines tested and were further investigated. The results confirmed their ability to inhibit, dose dependently, LPS-stimulated expression of the co-stimulatory molecules CD40 and/or CD86 and the production of the pro-inflammatory cytokines IL-1β, IL-6, IL-12 and TNFα. Our results demonstrate that DC maturation process can be targeted by semisynthetic DHA derivatives and TQ epimers and indicate the potential of these compounds as optimizable anti-inflammatory/immunomodulatory agents.

Mesenchymal stromal cells-derived small extracellular vesicles modulate DC function to suppress Th2 responses via IL-10 in patients with allergic rhinitis.

Mesenchymal stromal cells (MSCs) are well known for their immunoregulatory roles on allergic inflammation particularly by acting on T cells, B cells, and dendritic cells (DCs). MSC‐derived small extracellular vesicles (MSC‐sEV) are increasingly considered as one of the main factors for the effects of MSCs on immune responses. However, the effects of MSC‐sEV on DCs in allergic diseases remain unclear.MSC‐sEV were prepared from the induced pluripotent stem cells (iPSC)‐MSCs by anion‐exchange chromatography, and were characterized with the size, morphology, and specific markers. Human monocyte‐derived DCs were generated and cultured in the presence of MSC‐sEV to differentiate the so‐called sEV‐immature DCs (sEV‐iDCs) and sEV‐mature DCs (sEV‐mDCs), respectively. The phenotypes and the phagocytic ability of sEV‐iDCs were analyzed by flow cytometry. sEV‐mDCs were co‐cultured with isolated CD4+T cells or peripheral blood mononuclear cells (PBMCs) from patients with allergic rhinitis. The levels of Th1 and Th2 cytokines produced by T cells were examined by ELISA and intracellular flow staining. And the following mechanisms were further investigated.We demonstrated that MSC‐sEV inhibited the differentiation of human monocytes to iDCs with downregulation of the expression of CD40, CD80, CD86, and HLA‐DR, but had no effects on mDCs with these markers. However, MSC‐sEV treatment enhanced the phagocytic ability of mDCs. More importantly, using anti‐IL‐10 monoclonal antibody or IL‐10Rα blocking antibody, we identified that sEV‐mDCs suppressed the Th2 immune response by reducing the production of IL‐4, IL‐9, and IL‐13 via IL‐10. Furthermore, sEV‐mDCs increased the level of Treg cells.Our study identified that mDCs treated with MSC‐sEV inhibited the Th2 responses, providing novel evidence of the potential cell‐free therapy acting on DCs in allergic airway diseases.

Complement Promotes Gvhd through Suppressing Autophagy in Recipient Dendritic Cells after Allogeneic Hematopoietic Cell Transplantation in Mice

Graft-versus-host disease (GVHD) limits the success of allogeneic hematopoietic stem cell transplantation (allo-HCT). Traditional therapies have targeted T cells, yet immunostimulatory dendritic cells (DCs) are critical in the pathogenesis of GVHD. Autophagy is a self-degradative process for cytosolic components and is required for maintaining homeostasis after allo-HCT. Complement receptors C3aR/C5aR can regulate immune responses by translating information gathered by complement fluid phase sensors into cellular responses. C3aR/C5aR have been reported to activate the autophagy inhibitor mTOR in cells. While depletion of autophagy in recipient DCs aggravates GVHD severity, and enhancing autophagy represents as a promising approach for treating immunological diseases, it is not known how escalation of autophagy regulates DC-functionality in GVHD pathogenesis. In the current study, we found that deficiency of C3aR/C5aR signaling significantly upregulated mTOR-independent autophagy in DCs (Figure 1B), which is associated with increased apoptosis, and reduced activation and antigen presenting capacity of C3aR/C5aR-/-DCs (Figure 1, A-C).To evaluate the role of C3aR/C5aR in modulating DC function in GVHD pathogenesis, we compared the severity of GVHD in WT versus C3aR/C5aR-/- recipients using murine models of allo-HCT. C3aR/C5aR-/- recipients developed less severe GVHD than their WT counterparts, reflected by a significantly higher rate of survival and lower clinical scores (Figure 1D). Donor T-cell survival and Th1-differentiation were significantly decreased, whereas Treg generation was increased in C3aR/C5aR-/- recipients. Glycolytic activity of donor T cells was significantly abrogated in the absence of recipient C3aR/C5ar (Figure 1E). Donor T-cells expressed lower levels of chemokine receptors, CXCR3 and CCR6, which were likely contributed to the decreased migration of the effector T cells into GVHD target organs of C3aR/C5aR-/- recipients. Using chimeric recipients in which either the hematopoietic or non-hematopoietic compartment is deficient for C3aR/C5aR, we found that C3aR/C5aR in the recipient hematopoietic cells was primarily responsible for donor T-cell response and pathogenicity in GVHD. Transfusion of C3aR/C5aR-/- DCs along with allo-HCT mitigated GVHD severity, indicating that C3aR/5aR signaling in DCs plays a predominant role in the pathogenesis of GVHD. Elevated autophagy was required for the suppressive effect of C3aR/C5aR-/- DCs on GVHD as autophagy inhibitor chloroquine (CQ) reverted the GVHD-suppressive effect of C3aR/C5aR-/-DCs (Figure 1F). For translational purpose, we evaluated the therapeutic potential of a combination of C3aR and C5aR antagonists, and found that pharmacological blockade of C3aR/C5aR could effectively reduce GVHD severity while sparing GVL effect through persevering CD8 cytolytic activity.The current study reveals for the first time that escalation of autophagy in DCs is an effective therapeutic approach for the control of GVHD, and establishes and interaction between complement and autophagy in allo-HCT. We also provide a novel strategy of enhancing autophagy as a DC-based vaccination strategy for the control of GVHD after transplantation. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Antigen presentation in cancer: insights into tumour immunogenicity and immune evasion.

Immune checkpoint blockade, which blocks inhibitory signals of T cell activation, has shown tremendous success in treating cancer, although success still remains limited to a fraction of patients. To date, clinically effective CD8+ T cell responses appear to target predominantly antigens derived from tumour-specific mutations that accumulate in cancer, also called neoantigens. Tumour antigens are displayed on the surface of cells by class I human leukocyte antigens (HLA-I). To elicit an effective antitumour response, antigen presentation has to be successful at two distinct events: first, cancer antigens have to be taken up by dendritic cells (DCs) and cross-presented for CD8+ T cell priming. Second, the antigens have to be directly presented by the tumour for recognition by primed CD8+ T cells and killing. Tumours exploit multiple escape mechanisms to evade immune recognition at both of these steps. Here, we review the tumour-derived factors modulating DC function, and we summarize evidence of immune evasion by means of quantitative modulation or qualitative alteration of the antigen repertoire presented on tumours. These mechanisms include modulation of antigen expression, HLA-I surface levels, alterations in the antigen processing and presentation machinery in tumour cells. Lastly, as complete abrogation of antigen presentation can lead to natural killer (NK) cell-mediated tumour killing, we also discuss how tumours can harbour antigen presentation defects and still evade NK cell recognition.

Tropomodulin1 Expression Increases Upon Maturation in Dendritic Cells and Promotes Their Maturation and Immune Functions.

Dendritic cells (DCs) are the most potent antigen-presenting cells. Upon maturation, DCs express costimulatory molecules and migrate to the lymph nodes to present antigens to T cells. The actin cytoskeleton plays key roles in multiple aspects of DC functions. However, little is known about the mechanisms and identities of actin-binding proteins that control DC maturation and maturation-associated functional changes. Tropomodulin1 (Tmod1), an actin-capping protein, controls actin depolymerization and nucleation. We found that Tmod1 was expressed in bone marrow-derived immature DCs and was significantly upregulated upon lipopolysaccharide (LPS)-induced DC maturation. By characterizing LPS-induced mature DCs (mDCs) from Tmod1 knockout mice, we found that compared with Tmod1+/+ mDCs, Tmod1-deficient mDCs exhibited lower surface expression of costimulatory molecules and chemokine receptors and reduced secretion of inflammatory cytokines, suggesting that Tmod1 deficiency retarded DC maturation. Tmod1-deficient mDCs also showed impaired random and chemotactic migration, deteriorated T-cell stimulatory ability, and reduced F-actin content and cell stiffness. Furthermore, Tmod1-deficient mDCs secreted high levels of IFN-β and IL-10 and induced immune tolerance in an experimental autoimmune encephalomyelitis (EAE) mouse model. Mechanistically, Tmod1 deficiency affected TLR4 signaling transduction, resulting in the decreased activity of MyD88-dependent NFκB and MAPK pathways but the increased activity of the TRIF/IRF3 pathway. Rescue with exogenous Tmod1 reversed the effect of Tmod1 deficiency on TLR4 signaling. Therefore, Tmod1 is critical in regulating DC maturation and immune functions by regulating TLR4 signaling and the actin cytoskeleton. Tmod1 may be a potential target for modulating DC functions, a strategy that would be beneficial for immunotherapy for several diseases.

IL-18 Responsiveness Defines Limitations in Immune Help for Specialized FcRγ- NK Cells.

Despite being prolific innate killers, NK cells are also key helper cells in antiviral defense, influencing adaptive immune responses via interactions with dendritic cells (DCs). In addition to causing NK cell dysfunction, HIV-1 infection contributes to the expansion of a rare population of NK cells deficient in FcRγ (FcRγ-), an intracellular adaptor protein that associates with CD16. The implications of this inflated NK cell subset in treated HIV-1 infection remain unclear. In this study, we explored the helper function of human NK cells in chronic HIV-1 infection, with a particular focus on characterizing FcRγ- NK cells. Exposure of NK cells to innate DC-derived costimulatory factors triggered their helper activity, defined by their ability to produce IFN-γ and to drive the maturation of high IL-12-producing DCs. In this setting, however, FcRγ- NK cells were defective at producing the dominant DC-polarizing agent IFN-γ. The reduced responsiveness of FcRγ- NK cells to IL-18 in particular, which was attributable to impaired inducible expression of IL-18Rα, extended beyond an inability to produce IFN-γ, as FcRγ- NK cells showed limited potential to differentiate into CD16-/CD25+/CD83+ helper cells. Notwithstanding their deficiencies in responsiveness to innate environmental cues, FcRγ- NK cells responded robustly to adaptive Ab-mediated signaling through CD16. The presence of an expanded population of FcRγ- NK cells with a diminished capacity to respond to IL-18 and to effectively modulate DC function may contribute to disturbances in proper immune homeostasis associated with HIV-1 infection and to defects in the initiation of optimal adaptive antiviral responses.

Intestinal regulatory T cell induction by β-elemene alleviates the formation of fat tissue-related inflammation

SummaryThe role of the intestinal immune system in the inhibition of fat tissue-related inflammation by dietary material is yet to be elucidated. Oral administration of β-elemene, contained in various foodstuffs, downregulated expressions of inflammatory cytokines and increased Foxp3+CD4+ T cells in adipose tissue of obese mice. However, β-elemene did not affect the inflammatory response of adipose tissue in vitro, suggesting that the inhibition observed in vivo was not due to direct interactions of adipose tissue with β-elemene. Instead, β-elemene increased Foxp3+CD4+ T cell population enhancing gene expressions of transforming growth factor β 1, retinaldehyde dehydrogenase 2, integrin αvβ8, and interleukin-10 in intestinal dendritic cells (DCs) in vivo and in vitro. Taken together, this study suggested the therapeutic effects of β-elemene on treating experimental obesity-induced chronic inflammation by adjusting the balance of immune cell populations in fat tissue through the generation of regulatory T cells in the intestinal immune system by modulating DC function.

The Opposing Effect of Type I IFN on the T Cell Response by Non-modified mRNA-Lipoplex Vaccines Is Determined by the Route of Administration

mRNA-lipoplex vaccines are currently being explored in phase II clinical trials for the treatment of patients with advanced solid tumors. Mechanistically, these mRNA-lipoplex vaccines are characterized by the induction of type I interferon (IFN) centered innate responses. Earlier studies have identified type I IFNs as major regulators of the T cell response instigated by mRNA-lipoplex vaccines. However, stimulatory or, in contrast, profound inhibitory effects of type I IFNs were described depending on the study. In this mouse study, we demonstrated that the opposing roles of type I IFN signaling on the magnitude of the vaccine-evoked T cell responses is dependent on the route of mRNA-lipoplex administration and is regulated at the level of the T cells rather than indirectly through modulation of dendritic cell function. This study helps to understand the double-edged sword character of type I IFN induction upon mRNA-based vaccine treatment and may contribute to a more rational design of mRNA vaccination regimens.

Wnt Signaling Cascade in Dendritic Cells and Regulation of Anti-tumor Immunity.

Dendritic cells (DCs) control the strength and quality of antigen-specific adaptive immune responses. This is critical for launching a robust immunity against invading pathogens while maintaining a state of tolerance to self-antigens. However, this also represents a fundamental barrier to anti-tumor immune responses and cancer immunotherapy. DCs in the tumor microenvironment (TME) play a key role in this process. The factors in the TME and signaling networks that program DCs to a regulatory state are not fully understood. Recent advances point to novel mechanisms by which the canonical Wnt signaling cascade in DCs regulates immune suppression, and the same pathway in tumors is associated with the evasion of anti-tumor immunity. Here, we review these recent advances in the context of the pleiotropic effects of the Wnts in shaping anti-tumor immune responses by modulating DC functions. In addition, we will discuss how Wnt/β-catenin pathway in DCs can be targeted for successful cancer immunotherapy.

Cannabinoid Receptor 2 Modulates Maturation of Dendritic Cells and Their Capacity to Induce Hapten-Induced Contact Hypersensitivity.

Contact hypersensitivity (CHS) is an established animal model for allergic contact dermatitis. Dendritic cells (DCs) play an important role in the sensitization phase of CHS by initiating T cell responses to topically applied haptens. The cannabinoid receptors 1 (CB1) and 2 (CB2) modulate DC functions and inflammatory skin responses, but their influence on the capacity of haptenized DCs to induce CHS is still unknown. We found lower CHS responses to 2,4-dinitro-1-fluorobenzene (DNFB) in wild type (WT) mice after adoptive transfer of haptenized Cnr2−/− and Cnr1−/−/Cnr2−/− bone marrow (BM) DCs as compared to transfer of WT DCs. In contrast, induction of CHS was not affected in WT recipients after transfer of Cnr1−/− DCs. In vitro stimulated Cnr2−/− DCs showed lower CCR7 and CXCR4 expression when compared to WT cells, while in vitro migration towards the chemokine ligands was not affected by CB2. Upregulation of MHC class II and co-stimulatory molecules was also reduced in Cnr2−/− DCs. This study demonstrates that CB2 modulates the maturation phenotype of DCs but not their chemotactic capacities in vitro. These findings and the fact that CHS responses mediated by Cnr2−/− DCs are reduced suggest that CB2 is a promising target for the treatment of inflammatory skin conditions.

Intracellular Galectin-9 Controls Dendritic Cell Function by Maintaining Plasma Membrane Rigidity.

SummaryEndogenous extracellular Galectins constitute a novel mechanism of membrane protein organization at the cell surface. Although Galectins are also highly expressed intracellularly, their cytosolic functions are poorly understood. Here, we investigated the role of Galectin-9 in dendritic cell (DC) surface organization and function. By combining functional, super-resolution and atomic force microscopy experiments to analyze membrane stiffness, we identified intracellular Galectin-9 to be indispensable for plasma membrane integrity and structure in DCs. Galectin-9 knockdown studies revealed intracellular Galectin-9 to directly control cortical membrane structure by modulating Rac1 activity, providing the underlying mechanism of Galectin-9-dependent actin cytoskeleton organization. Consequent to its role in maintaining plasma membrane structure, phagocytosis studies revealed that Galectin-9 was essential for C-type-lectin receptor-mediated pathogen uptake by DCs. This was confirmed by the impaired phagocytic capacity of Galectin-9-null murine DCs. Together, this study demonstrates a novel role for intracellular Galectin-9 in modulating DC function, which may be evolutionarily conserved.

Dendritic cells in cancer immunology and immunotherapy.

Dendritic cells (DCs) are a diverse group of specialized antigen-presenting cells with key roles in the initiation and regulation of innate and adaptive immune responses. As such, there is currently much interest in modulating DC function to improve cancer immunotherapy. Many strategies have been developed to target DCs in cancer, such as the administration of antigens with immunomodulators that mobilize and activate endogenous DCs, as well as the generation of DC-based vaccines. A better understanding of the diversity and functions of DC subsets and of how these are shaped by the tumour microenvironment could lead to improved therapies for cancer. Here we will outline how different DC subsets influence immunity and tolerance in cancer settings and discuss the implications for both established cancer treatments and novel immunotherapy strategies.

IL-10 Dampens the Th1 and Tc Activation through Modulating DC Functions in BCG Vaccination.

BCG, the only registered vaccine against Mycobacterial Tuberculosis (TB) infection, has been questioned for its protective efficacy for decades. Although lots of efforts were made to improve the BCG antigenicity, few studies were devoted to understand the role of host factors in the variability of the BCG protection. Using the IL-10KO mice and pulmonary tuberculosis infection model, we have addressed the role of IL-10 in the BCG vaccination efficacy. The data showed that IL-10-deficient dendritic cells (DCs) could promote the immune responses through upregulation of the surface costimulatory molecule expression and play an orchestra role through activating CD4+T cell. IL-10-deficient mice had higher IFN γ, TNF α, and IL-6 production after BCG vaccination, which was consistent with the higher proportion of IFN γ+CD3+, IFN γ+CD4+, and IFN γ+CD8+ T cells in the spleen. Particularly, the BCG-vaccinated IL-10KO mice showed less inflammation after TB challenge compared to WT mice, which was supported by the promoted Th1 and Tc, as well as the downregulated Treg responses in IL-10 deficiency. In a conclusion, we demonstrated the negative relationship between Th1/Tc responses with IL-10 production. IL-10 deficiency restored the type 1 immune response through DC activation, which provided better protection against TB infection. Hence, our study offers the first experimental evidence that, contrary to the modulation of BCG, host immunity plays a critical role in the BCG protective efficacy against TB.

Genome-Wide Transcriptional Analysis Reveals Novel AhR Targets That Regulate Dendritic Cell Function during Influenza A Virus Infection.

Activation of the ligand inducible aryl hydrocarbon receptor (AhR) during primary influenza A virus infection diminishes host responses by negatively regulating the ability of dendritic cells (DC) to prime naive CD8+ T cells, which reduces the generation of CTL. However, AhR-regulated genes and signaling pathways in DCs are not fully known. In this study, we used unbiased gene expression profiling to identify differentially expressed genes and signaling pathways in DCs that are modulated by AhR activation in vivo. Using the prototype AhR agonist TCDD, we identified the lectin receptor Cd209a (DC-SIGN) and chemokine Ccl17 as novel AhR target genes. We further show the percentage of DCs expressing CD209a on their surface was significantly decreased by AhR activation during infection. Whereas influenza A virus infection increased CCL17 protein levels in the lung and lung-draining lymph nodes, this was significantly reduced following AhR activation. Targeted excision of AhR in the hematopoietic compartment confirmed AhR is required for downregulation of CCL17 and CD209a. Loss of AhR's functional DNA-binding domain demonstrates that AhR activation alone is necessary but not sufficient to drive downregulation. AhR activation induced similar changes in gene expression in human monocyte-derived DCs. Analysis of the murine and human upstream regulatory regions of Cd209a and Ccl17 revealed a suite of potential transcription factor partners for AhR, which may coregulate these genes in vivo. This study highlights the breadth of AhR-regulated pathways within DCs, and that AhR likely interacts with other transcription factors to modulate DC functions during infection.

Porcine Dendritic Cells and Viruses: An Update.

Several viral infections of swine are responsible for major economic losses and represent a threat to the swine industry worldwide. New tools are needed to prevent and control endemic, emerging, and re-emerging viral diseases. Dendritic cells (DC) play a central role in linking the innate and adaptive arms of the immune system, so knowledge regarding their interaction with pathogens is necessary to understand the mechanisms underlying diseases pathogenesis and protection. In the first part of this review, we provide an update on the heterogeneous cell subsets that comprise the porcine DC family. In the second part of this review, we provide an overview of how three viruses, affecting pork production at a global level, African swine fever virus (ASFV), classical swine fever virus (CSFV), and porcine circovirus 2 (PCV2), modulate DC function.

MTOR Inhibitors Can Enhance the Anti-Tumor Effects of DNA Vaccines through Modulating Dendritic Cell Function in the Tumor Microenvironment.

The life span of dendritic cells (DCs) can become short following induced activation, which is associated with metabolic transition due to the regulation of mechanistic target of rapamycin (mTOR). The purpose of this study was to investigate the potential of inhibiting mTOR to modulate DC functions for elevating the anti-tumor effects of DNA vaccines. Therefore, the influences of various inhibitors of mTOR (mTORi) on the expressions of DC maturation markers, the abilities of antigen presenting and processing of BMM-derived DCs and the tumor killing effects of E7-specific CD8+ T lymphocytes activated by BMM-derived DCs were in vitro examined. The anti-tumor effects of connective tissue growth factor (CTGF)/E7 DNA vaccine and/or mTORi were also in vivo analyzed. In our study, suppressive effects of mTORi on the DC maturation markers expressed on BMMCs could be reversed. The mTORi-treated mature BMM-derived DCs tended to be non-apoptotic. These mTORi-treated BMM-derived DCs could have better antigen presenting and processing abilities. The E7-specific cytotoxic CD8+ T lymphocytes could have more potent tumoricidal activity following activation of mTORi-treated BMM-derived DCs. For tumor-bearing mice, those treated with CTGF/E7 DNA vaccine and mTORi indeed can have higher percentages of mature DCs in the TME, better disease control and longer survivals. Consequently, application of mTORi can be a pharmacological approach for temporally increasing life span, antigen presenting and antigen processing of DCs to strengthen the therapeutic outcome of cancer immunotherapy.