Dendritic cells (DCs) are central players of the immune response. To date, DC-based immunotherapy is explored worldwide in clinical vaccination trials with cancer patients, predominantly with ex ...vivo-cultured monocyte-derived DCs (moDCs). However, the extensive culture period and compounds required to differentiate them into DCs may negatively affect their immunological potential. Therefore, it is attractive to consider alternative DC sources, such as blood DCs. Two major types of naturally occurring DCs circulate in peripheral blood, myeloid DCs (mDCs) and plasmacytoid (pDCs). These DC subsets express different surface molecules and are suggested to have distinct functions. Besides scavenging pathogens and presenting antigens, DCs secrete cytokines, all of which is vital for both the acquired and the innate immune system. These immunological functions relate to Toll-like receptors (TLRs) expressed by DCs. TLRs recognize pathogen-derived products and subsequently provoke DC maturation, antigen presentation and cytokine secretion. However, not every TLR is expressed on each DC subset nor causes the same effects when activated. Considering the large amount of clinical trials using DC-based immunotherapy for cancer patients and the decisive role of TLRs in DC maturation, this review summarizes TLR expression in different DC subsets in relation to their function. Emphasis will be given to the therapeutic potential of TLR-matured DC subsets for DC-based immunotherapy.
Tumor-infiltrating dendritic cells (DCs) assume varied functional states that impact anti-tumor immunity. To delineate the DC states associated with productive anti-tumor T cell immunity, we compared ...spontaneously regressing and progressing tumors. Tumor-reactive CD8+ T cell responses in Batf3−/− mice lacking type 1 DCs (DC1s) were lost in progressor tumors but preserved in regressor tumors. Transcriptional profiling of intra-tumoral DCs within regressor tumors revealed an activation state of CD11b+ conventional DCs (DC2s) characterized by expression of interferon (IFN)-stimulated genes (ISGs) (ISG+ DCs). ISG+ DC-activated CD8+ T cells ex vivo comparably to DC1. Unlike cross-presenting DC1, ISG+ DCs acquired and presented intact tumor-derived peptide-major histocompatibility complex class I (MHC class I) complexes. Constitutive type I IFN production by regressor tumors drove the ISG+ DC state, and activation of MHC class I-dressed ISG+ DCs by exogenous IFN-β rescued anti-tumor immunity against progressor tumors in Batf3−/− mice. The ISG+ DC gene signature is detectable in human tumors. Engaging this functional DC state may present an approach for the treatment of human disease.
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•IFN-I induces a stimulatory DC2 state (ISG+ DCs) that activates CD8+ T cells•B2M−/− ISG+ DCs acquire and present tumor-derived pMHC class I complexes•Precluding MHC class I transfer to ISG+ DCs ablates T cell responses in Batf3−/− mice•ISG+ DCs can be induced by exogenous IFN-β addition to drive anti-tumor immunity
Tumor-infiltrating dendritic cells (DCs) are central to the anti-tumor immune response. Duong et al. reveal an activation state of CD11b+ conventional DCs (DC2) characterized by expression of interferon (IFN)-stimulated genes (ISG+ DCs) and capable of acquiring and presenting intact tumor-derived peptide-MHC class I complexes. ISG+ DCs can activate CD8+ T cells and promote protective anti-tumor immunity in the absence of DC1.
DCs play a pivotal role in orchestrating innate and adaptive antitumor immunity. Activated DCs can produce large amounts of various proinflammatory cytokines, initiate T‐cell responses, and exhibit ...direct cytotoxicity against tumor cells. They also efficiently enhance the antitumoral properties of NK cells and T lymphocytes. Based on these capabilities, immunogenic DCs promote tumor elimination and are associated with improved survival of patients. Furthermore, they can essentially contribute to the clinical efficacy of immunotherapeutic strategies for cancer patients. However, depending on their intrinsic properties and the tumor microenvironment, DCs can be rendered dysfunctional and mediate tolerance by producing immunosuppressive cytokines and activating Treg cells. Such tolerogenic DCs can foster tumor progression and are linked to poor prognosis of patients. Here, we focus on recent studies exploring the phenotype, functional orientation, and clinical relevance of tumor‐infiltrating conventional DC1, conventional DC2, plasmacytoid DCs, and monocyte‐derived DCs in translational and clinical settings. In addition, recent findings demonstrating the influence of DCs on the efficacy of immunotherapeutic strategies are summarized.
Immunostimulatory DCs induce and maintain effective innate and adaptive antitumor immune responses, linking them to an improved clinical outcome of cancer patients and response to immunotherapy. Conversely, tolerogenic DCs essentially contribute to an immunosuppressive tumor microenvironment and are associated with reduced survival of cancer patients.
Plasmacytoid dendritic cells (pDCs) are specialized in rapid and massive secretion of type I interferon (IFN-α/β) in response to foreign nucleic acids. Combined with their antigen presentation ...capacity, this powerful functionality enables pDCs to orchestrate innate and adaptive immune responses. pDCs combine features of both lymphocytes and classical dendritic cells and display unique molecular adaptations to nucleic acid sensing and IFN production. In the decade since the identification of the pDC as a distinct immune cell type, our understanding of its molecular underpinnings and role in immunity has progressed rapidly. Here we review select aspects of pDC biology including cell fate establishment and plasticity, specific molecular mechanisms of pDC function, and the role of pDCs in T cell responses, antiviral immunity, and autoimmune diseases. Important unresolved questions remain in these areas, promising exciting times in pDC research for years to come.
A breakdown in intestinal homeostasis can result in chronic inflammatory diseases of the gut including inflammatory bowel disease, coeliac disease and allergy. Dendritic cells, through their ability ...to orchestrate protective immunity and immune tolerance in the host, have a key role in shaping the intestinal immune response. The mechanisms through which dendritic cells can respond to environmental cues in the intestine and select appropriate immune responses have until recently been poorly understood. Here, we review recent work that is beginning to identify factors responsible for intestinal conditioning of dendritic-cell function and the subsequent decision between tolerance and immunity in the intestine.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Lymphoid organs, in which antigen presenting cells (APCs) are in close proximity to T cells, are the ideal microenvironment for efficient priming and amplification of T-cell responses. However, the ...systemic delivery of vaccine antigens into dendritic cells (DCs) is hampered by various technical challenges. Here we show that DCs can be targeted precisely and effectively in vivo using intravenously administered RNA-lipoplexes (RNA-LPX) based on well-known lipid carriers by optimally adjusting net charge, without the need for functionalization of particles with molecular ligands. The LPX protects RNA from extracellular ribonucleases and mediates its efficient uptake and expression of the encoded antigen by DC populations and macrophages in various lymphoid compartments. RNA-LPX triggers interferon-α (IFNα) release by plasmacytoid DCs and macrophages. Consequently, DC maturation in situ and inflammatory immune mechanisms reminiscent of those in the early systemic phase of viral infection are activated. We show that RNA-LPX encoding viral or mutant neo-antigens or endogenous self-antigens induce strong effector and memory T-cell responses, and mediate potent IFNα-dependent rejection of progressive tumours. A phase I dose-escalation trial testing RNA-LPX that encode shared tumour antigens is ongoing. In the first three melanoma patients treated at a low-dose level, IFNα and strong antigen-specific T-cell responses were induced, supporting the identified mode of action and potency. As any polypeptide-based antigen can be encoded as RNA, RNA-LPX represent a universally applicable vaccine class for systemic DC targeting and synchronized induction of both highly potent adaptive as well as type-I-IFN-mediated innate immune mechanisms for cancer immunotherapy.
Gut microbiota-mediated secondary bile acids (BAs) play an important role in energy balance and host metabolism via G protein-coupled receptors and/or nuclear receptors. Emerging evidence suggests ...that BAs are important for maintaining innate immune responses via these receptors. However, the effect of BAs on autoimmune uveitis is still unknown. Here, we demonstrate decreased microbiota-related secondary BA concentration in feces and serum of animals with experimental autoimmune uveitis (EAU). Restoration of the gut BAs pool attenuates severity of EAU in association with inhibition of nuclear factor κB (NF-κB)-related pro-inflammatory cytokines in dendritic cells (DCs). TGR5 deficiency partially reverses the inhibitory effect of deoxycholic acid (DCA) on DCs. TGR5 signaling also inhibits NF-κB activation via the cyclic AMP (cAMP)-protein kinase A (PKA) pathway in DCs. Additionally, both DCA and TGR5 agonists inhibit human monocyte-derived DC activation. Taken together, our results suggest that BA metabolism plays an important role in adaptive immune responses and might be a therapeutic target in autoimmune uveitis.
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•Secondary bile acids reduce severity of experimental autoimmine uveitis (EAU) in mice•Altered bile acids are correlated with gut microbiota composition in EAU mice•Deoxycholic acid regulates the function of DCs via the TGR5-cAMP-PKA pathway
Hu et al. reveal that gut microbiota-related dysmetabolism of bile acids is involved in the development of experimental autoimmune uveitis (EAU). Secondary bile acids are reduced in the feces and serum of EAU mice. Secondary bile acids regulate function of dendritic cells via the TGR5-cAMP-PKA pathway in EAU mice.
Dendritic cells (DC) are central to regulating innate and adaptive immune responses. Strategies that modify DC function provide new therapeutic opportunities in autoimmune diseases and ...transplantation. Current pharmacological approaches can alter DC phenotype to induce tolerogenic DC (tolDC), a maturation-resistant DC subset capable of directing a regulatory immune response that are being explored in current clinical trials. The classical phenotypic characterization of tolDC is limited to cell-surface marker expression and anti-inflammatory cytokine production, although these are not specific. TolDC may be better defined using gene signatures, but there is no consensus definition regarding genotypic markers. We address this shortcoming by analyzing available transcriptomic data to yield an independent set of differentially expressed genes that characterize human tolDC. We validate this transcriptomic signature and also explore gene differences according to the method of tolDC generation. As well as establishing a novel characterization of tolDC, we interrogated its translational utility
, demonstrating this geneset was enriched in the liver, a known tolerogenic organ. Our gene signature will potentially provide greater understanding regarding transcriptional regulators of tolerance and allow researchers to standardize identification of tolDC used for cellular therapy in clinical trials.
Dendritic cells (DCs) play essential roles in innate and adaptive immunity and show high heterogeneity and intricate ontogeny. Advances in high-throughput sequencing technologies, particularly ...single-cell RNA sequencing (scRNA-seq), have improved the understanding of DC subsets. In this review, we discuss in detail the remarkable perspectives in DC reclassification and ontogeny as revealed by scRNA-seq. Moreover, the heterogeneity and multifunction of DCs during diseases as determined by scRNA-seq are described. Finally, we provide insights into the challenges and future trends in scRNA-seq technologies and DC research.
The phenotypic and functional dichotomy between IRF8+ type 1 and IRF4+ type 2 conventional dendritic cells (cDC1s and cDC2s, respectively) is well accepted; it is unknown how robust this dichotomy is ...under inflammatory conditions, when additionally monocyte-derived cells (MCs) become competent antigen-presenting cells (APCs). Using single-cell technologies in models of respiratory viral infection, we found that lung cDC2s acquired expression of the Fc receptor CD64 shared with MCs and of IRF8 shared with cDC1s. These inflammatory cDC2s (inf-cDC2s) were superior in inducing CD4+ T helper (Th) cell polarization while simultaneously presenting antigen to CD8+ T cells. When carefully separated from inf-cDC2s, MCs lacked APC function. Inf-cDC2s matured in response to cell-intrinsic Toll-like receptor and type 1 interferon receptor signaling, upregulated an IRF8-dependent maturation module, and acquired antigens via convalescent serum and Fc receptors. Because hybrid inf-cDC2s are easily confused with monocyte-derived cells, their existence could explain why APC functions have been attributed to MCs.
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•Type I interferon drives differentiation of inf-cDC2s that closely resemble MCs•Inf-cDC2s prime CD4+ and CD8+ T cells, whereas MCs lack APC function•Inf-cDC2s internalize antibody-complexed antigen via Fc receptors•IRF8 controls maturation gene module in inf-cDC2s
The dichotomy between type 1 and 2 conventional DCs under steady-state conditions is well defined. Bosteels et al. demonstrate that, upon inflammation, cDC2s acquire a hybrid inf-cDC2 phenotype, sharing phenotype, gene expression, and function with cDC1s and monocyte-derived cells, to optimally boost CD4 and CD8 immunity via Fc receptors.
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