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Long non‐coding RNAs (lncRNAs) and dendritic cells (DC) play crucial roles in the development of acute coronary syndrome (ACS); however, the mechanisms remain unclear. To investigate this, we analysed the differentially expressed lncRNAs in monocyte‐derived DCs (moDCs) from patients with ACS. Peripheral blood mononuclear cells were transformed into moDCs. Cellular morphology and expression levels of moDC‐specific markers (CD80, CD86, CD11c, CD14 and HLA‐DR) were analysed using electron microscopy (EM) and flow cytometry (FCM), respectively. Differentially expressed lncRNAs and their functions were predicted using gene sequencing, gene ontology and the Kyoto Encyclopedia of Genes and Genomes. The expression levels of markers, signalling pathway molecules (p‐PI3K and p‐AKT), inflammatory cytokines (IL‐6 and IL‐12p70) and target gene (C‐C motif chemokine ligand (CCL) 15 and CCL14) were analysed by overexpression or silencing of candidate lncRNAs. EM revealed the cells to be suspended in dendritic pseudopodia. CD11c and HLA‐DR were upregulated, while CD80 and CD86 were downregulated. Comparison between the UA versus ST group showed the highest number of differentially expressed lncRNAs (n = 113), followed by UA versus NST (n = 115), CON versus NST (n = 49) and CON versus ST (n = 35); however, the number was low for CON versus UA and ST versus NST groups. moDC‐specific marker expression, signalling pathway molecules, inflammatory cytokines and CCL14 were upregulated following lentiviral overexpression of smart silencer‐CCL15‐CCL14; however, expression levels decreased following transfection with siRNA. The morphology, function and lncRNA expression of moDCs differ depending on the type of ACS. The differentially expressed lncRNAs, particularly CCL15‐CCL14, regulate the function of moDCs. Thus, our study provides new insights regarding the role of lncRNAs in ACS and indicates the potential use of CCL15‐CCL14 as a novel diagnostic marker and therapeutic target.

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.

Viruses may interfere with the MHC class I antigen presentation pathway in order to avoid CD8+ T cell‐mediated immunity. A key target within this pathway is the peptide transporter TAP. This transporter plays a central role in MHC class I‐mediated peptide presentation of endogenous antigens. In addition, TAP plays a role in antigen cross‐presentation of exogenously derived antigens by dendritic cells (DCs). In this study, a soluble form of the cowpox virus TAP inhibitor CPXV012 is synthesized for exogenous delivery into the antigen cross‐presentation route of human monocyte‐derived (mo)DCs. We show that soluble CPXV012 localizes to TAP+ compartments that carry internalized antigen and is a potent inhibitor of antigen cross‐presentation. CPXV012 stimulates the prolonged deposition of antigen fragments in storage compartments of moDCs, as a result of reduced endosomal acidification and reduced antigen proteolysis when soluble CPXV012 is present. Thus, a dual function can be proposed for CPXV012: inhibition of TAP‐mediated peptide transport and inhibition of endosomal antigen degradation. We propose this second function for soluble CPXV012 can serve to interfere with antigen cross‐presentation in a peptide transport‐independent manner. Human monocyte‐derived dendritic cells (MoDCs) efficiently cross‐present antigen to CD8+ T‐cells, which is diminished in the presence of soluble cowpox virus protein 12 (sCPXV012). Our findings indicate that sCPXV012, when taken up into antigen storage compartments by MoDCs, prevents endosomal acidification and subsequent degradation of antigen into smaller peptides.

Why and when the immune system skews to Th2 mediated allergic immune responses is still poorly characterized. With two homologous lipocalins, the major respiratory dog allergen Can f 1 and the human endogenous, non‐allergenic Lipocalin‐1, we investigated their impact on human monocyte‐derived dendritic cells (DC). The two lipocalins had differential effects on DC according to their allergenic potential. Compared to Lipocalin‐1, Can f 1 persistently induced lower levels of the Th1 skewing maturation marker expression, tryptophan breakdown and interleukin (IL)‐12 production in DC. As a consequence, T cells stimulated by DC treated with Can f 1 produced more of the Th2 signature cytokine IL‐13 and lower levels of the Th1 signature cytokine interferon‐γ than T cells stimulated by Lipocalin‐1 treated DC. These data were partially verified by a second pair of homologous lipocalins, the cat allergen Fel d 4 and its putative human homologue major urinary protein. Our data indicate that the crosstalk of DC with lipocalins alone has the potential to direct the type of immune response to these particular antigens. A global gene expression analysis further supported these results and indicated significant differences in intracellular trafficking, sorting and antigen presentation pathways when comparing Can f 1 and Lipocalin‐1 stimulated DC. With this study we contribute to a better understanding of the induction phase of a Th2 immune response.

Dendritic cells (DC) are professional antigen presenting cells, uniquely able to induce naïve T cell activation and effector differentiation. They are, likewise, involved in the induction and maintenance of immune tolerance in homeostatic conditions. Their phenotypic and functional heterogeneity points to their great plasticity and ability to modulate, according to their microenvironment, the acquired immune response and, at the same time, makes their precise classification complex and frequently subject to reviews and improvement. This review will present general aspects of the DC physiology and classification and will address their potential and actual uses in the management of human disease, more specifically cancer, as therapeutic and monitoring tools. New combination treatments with the participation of DC will be also discussed.

Natural killer (NK) cells recognize and kill target cells undergoing different types of stress. NK cells are also capable of modulating immune responses. In particular, they regulate T cell functions. Small RNA next-generation sequencing of resting and activated human NK cells and their secreted extracellular vesicles (EVs) led to the identification of a specific repertoire of NK-EV-associated microRNAs and their post-transcriptional modifications signature. Several microRNAs of NK-EVs, namely miR-10b-5p, miR-92a-3p, and miR-155-5p, specifically target molecules involved in Th1 responses. NK-EVs promote the downregulation of GATA3 mRNA in CD4 + T cells and subsequent TBX21 de-repression that leads to Th1 polarization and IFN-γ and IL-2 production. NK-EVs also have an effect on monocyte and moDCs (monocyte-derived dendritic cells) function, driving their activation and increased presentation and costimulatory functions. Nanoparticle-delivered NK-EV microRNAs partially recapitulate NK-EV effects in mice. Our results provide new insights on the immunomodulatory roles of NK-EVs that may help to improve their use as immunotherapeutic tools.

Cardiovascular disease is the leading cause of mortality worldwide, and atherosclerosis the principal factor underlying cardiovascular events. Atherosclerosis is a chronic inflammatory disease characterized by endothelial dysfunction, intimal lipid deposition, smooth muscle cell proliferation, cell apoptosis and necrosis, and local and systemic inflammation, involving key contributions to from innate and adaptive immunity. The balance between proatherogenic inflammatory and atheroprotective anti-inflammatory responses is modulated by a complex network of interactions among vascular components and immune cells, including monocytes, macrophages, dendritic cells, and T, B, and foam cells; these interactions modulate the further progression and stability of the atherosclerotic lesion. In this review, we take a global perspective on existing knowledge about the pathogenesis of immune responses in the atherosclerotic microenvironment and the interplay between the major innate and adaptive immune factors in atherosclerosis. Studies such as this are the basis for the development of new therapies against atherosclerosis.

Dendritic cell (DC)-based immunotherapy employs the patients' immune system to fight neoplastic lesions spread over the entire body. This makes it an important therapy option for patients suffering from metastatic melanoma, which is often resistant to chemotherapy. However, conventional cellular vaccination approaches, based on monocyte-derived DCs (moDCs), only achieved modest response rates despite continued optimization of various vaccination parameters. In addition, the generation of moDCs requires extensive ex vivo culturing conceivably hampering the immunogenicity of the vaccine. Recent studies, thus, focused on vaccines that make use of primary DCs. Though rare in the blood, these naturally circulating DCs can be readily isolated and activated thereby circumventing lengthy ex vivo culture periods. The first clinical trials not only showed increased survival rates but also the induction of diversified anti-cancer immune responses. Upcoming treatment paradigms aim to include several primary DC subsets in a single vaccine as pre-clinical studies identified synergistic effects between various antigen-presenting cells.

Glatiramer acetate (GA) is the first-line therapy for relapsing-remitting multiple sclerosis (MS) and is increasingly demonstrating promising therapeutic benefits in a range of other conditions. Despite its extensive use, the precise pharmacological mechanism of GA remains unclear. In addition to T and B cells, dendritic cells (DCs) and monocytes play significant roles in the neuroinflammation associated with MS, positioning them as potential initial targets for GA. Here, we investigated GA’s influence on the differentiation of human monocytes from healthy donors into monocyte-derived dendritic cells (moDCs) and assessed their activation status. Our results indicate that GA treatment does not hinder the differentiation of monocytes into moDCs or macrophages. Notably, we observed a significant increase in the expression of molecules required for antigen recognition, presentation, and co-stimulation in GA-treated moDCs. Conversely, there was a significant downregulation of CD1a, which is crucial for activating auto-aggressive T cells that respond to the lipid components of myelin. Furthermore, GA treatment resulted in an increased expression of CD68 on both CD14+CD16+ and CD14+CD16− monocyte subsets. These in vitro findings suggest that GA treatment does not impede the generation of moDCs under inflammatory conditions; however, it may modify their functional characteristics in potentially beneficial ways. This provides a basis for future clinical studies in MS patients to elucidate its precise mode of action.

In response to microbial stimulation, monocytes can differentiate into macrophages or monocyte-derived dendritic cells (MoDCs) but the molecular requirements guiding these possible fates are poorly understood. In addition, the physiological importance of MoDCs in the host cellular and immune responses to microbes remains elusive. Here, we demonstrate that the nuclear orphan receptor NR4A3 is required for the proper differentiation of MoDCs but not for other types of DCs. Indeed, the generation of DC-SIGN⁺ MoDCs in response to LPS was severely impaired in Nr4a3−/− mice, which resulted in the inability to mount optimal CD8⁺ T cell responses to gram-negative bacteria. Transcriptomic analyses revealed that NR4A3 is required to skew monocyte differentiation toward MoDCs, at the expense of macrophages, and allows the acquisition of migratory characteristics required for MoDC function. Altogether, our data identify that the NR4A3 transcription factor is required to guide the fate of monocytes toward MoDCs.