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The Journal of Experimental Medicine Oct 2023Cytokines produced in association with tumors can impair antitumor immune responses by reducing the abundance of type 1 conventional dendritic cells (cDC1), but the...
Cytokines produced in association with tumors can impair antitumor immune responses by reducing the abundance of type 1 conventional dendritic cells (cDC1), but the mechanism remains unclear. Here, we show that tumor-derived IL-6 generally reduces cDC development but selectively impairs cDC1 development in both murine and human systems through the induction of C/EBPβ in the common dendritic cell progenitor (CDP). C/EBPβ and NFIL3 compete for binding to sites in the Zeb2 -165 kb enhancer and support or repress Zeb2 expression, respectively. At homeostasis, pre-cDC1 specification occurs upon Nfil3 induction and consequent Zeb2 suppression. However, IL-6 strongly induces C/EBPβ expression in CDPs. Importantly, the ability of IL-6 to impair cDC development is dependent on the presence of C/EBPβ binding sites in the Zeb2 -165 kb enhancer, as this effect is lost in Δ1+2+3 mutant mice in which these binding sites are mutated. These results explain how tumor-associated IL-6 suppresses cDC1 development and suggest therapeutic approaches preventing abnormal C/EBPβ induction in CDPs may help reestablish cDC1 development to enhance antitumor immunity.
Topics: Humans; Animals; Mice; Interleukin-6; Binding Sites; Cytokines; Dendritic Cells; Homeostasis
PubMed: 37432392
DOI: 10.1084/jem.20221757 -
Nature Biomedical Engineering May 2024Lipid nanoparticles (LNPs) can be designed to potentiate cancer immunotherapy by promoting their uptake by antigen-presenting cells, stimulating the maturation of these...
Lipid nanoparticles (LNPs) can be designed to potentiate cancer immunotherapy by promoting their uptake by antigen-presenting cells, stimulating the maturation of these cells and modulating the activity of adjuvants. Here we report an LNP-screening method for the optimization of the type of helper lipid and of lipid-component ratios to enhance the delivery of tumour-antigen-encoding mRNA to dendritic cells and their immune-activation profile towards enhanced antitumour activity. The method involves screening for LNPs that enhance the maturation of bone-marrow-derived dendritic cells and antigen presentation in vitro, followed by assessing immune activation and tumour-growth suppression in a mouse model of melanoma after subcutaneous or intramuscular delivery of the LNPs. We found that the most potent antitumour activity, especially when combined with immune checkpoint inhibitors, resulted from a coordinated attack by T cells and NK cells, triggered by LNPs that elicited strong immune activity in both type-1 and type-2 T helper cells. Our findings highlight the importance of optimizing the LNP composition of mRNA-based cancer vaccines to tailor antigen-specific immune-activation profiles.
Topics: Animals; Nanoparticles; Mice; Mice, Inbred C57BL; T-Lymphocytes, Helper-Inducer; Dendritic Cells; Lipids; Immunotherapy; Cancer Vaccines; Female; Melanoma, Experimental; Antigens, Neoplasm; RNA, Messenger; Liposomes
PubMed: 38082180
DOI: 10.1038/s41551-023-01131-0 -
Arthritis Research & Therapy Oct 2023Rheumatoid arthritis (RA) is a chronic inflammatory disease characterised by joint pain and swelling, synovial hyperplasia, cartilage damage, and bone destruction. The... (Review)
Review
Rheumatoid arthritis (RA) is a chronic inflammatory disease characterised by joint pain and swelling, synovial hyperplasia, cartilage damage, and bone destruction. The mechanisms of dendritic cell (DC) and T cell-mediated crosstalk have gradually become a focus of attention. DCs regulate the proliferation and differentiation of CD4 T cell subtypes through different cytokines, surface molecules, and antigen presentation. DC-T cell crosstalk also blocks antigen presentation by DCs, ultimately maintaining immune tolerance. DC-T cell crosstalk mainly involves chemokines, surface molecules (TonEBP, NFATc1), the PD-L1/PD-1 signalling axis, and the TGF-β signalling axis. In addition, DC-T cell crosstalk in RA is affected by glycolysis, reactive oxygen species, vitamin D, and other factors. These factors lead to the formation of an extremely complex regulatory network involving various mechanisms. This article reviews the key immune targets of DC-T cell crosstalk and elucidates the mechanism of DC-T cell crosstalk in RA to provide a basis for the treatment of patients with RA.
Topics: Humans; T-Lymphocytes; Arthritis, Rheumatoid; Cytokines; Signal Transduction; Dendritic Cells
PubMed: 37798668
DOI: 10.1186/s13075-023-03159-8 -
Journal of Leukocyte Biology Nov 2023Lysosomal compartments undergo extensive remodeling during dendritic cell (DC) activation to meet the dynamic functional requirements of DCs. Instead of being regarded... (Review)
Review
Lysosomal compartments undergo extensive remodeling during dendritic cell (DC) activation to meet the dynamic functional requirements of DCs. Instead of being regarded as stationary and digestive organelles, recent studies have increasingly appreciated the versatile roles of lysosomes in regulating key aspects of DC biology. Lysosomes actively control DC motility by linking calcium efflux to the actomyosin contraction, while enhanced DC lysosomal membrane permeability contributes to the inflammasome activation. Besides, lysosomes provide a platform for the transduction of innate immune signaling and the intricate host-pathogen interplay. Lysosomes and lysosome-associated structures are also critically engaged in antigen presentation and cross-presentation processes, which are pivotal for the induction of antigen-specific adaptive immune response. Through the current review, we emphasize that lysosome targeting strategies serve as vital DC-based immunotherapies in fighting against tumor, infectious diseases, and autoinflammatory disorders.
Topics: Dendritic Cells; Antigen Presentation; Cross-Priming; Signal Transduction; Lysosomes
PubMed: 37774493
DOI: 10.1093/jleuko/qiad117 -
Kidney International Sep 2023There is still no established treatment for acute kidney injury (AKI), and the intervention of AKI remains limited to supportive treatments. Li et al. demonstrated the...
There is still no established treatment for acute kidney injury (AKI), and the intervention of AKI remains limited to supportive treatments. Li et al. demonstrated the mechanism by which immune tolerance by dendritic cell ameliorates AKI in a mouse ischemia-reperfusion injury model. The phase I/II clinical trials of tolerogenic dendritic cell therapy have been conducted for kidney transplantation, so it is expected to have potential as a cell therapy for AKI in the future.
Topics: Animals; Mice; Acute Kidney Injury; Cell- and Tissue-Based Therapy; Disease Models, Animal; Kidney Transplantation; Dendritic Cells
PubMed: 37599014
DOI: 10.1016/j.kint.2023.06.015 -
Emerging Microbes & Infections Dec 2023The persistent pandemic of coronavirus disease in 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) currently poses a major... (Review)
Review
The persistent pandemic of coronavirus disease in 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) currently poses a major infectious threat to public health around the world. COVID-19 is an infectious disease characterized by strong induction of inflammatory cytokines, progressive lung inflammation, and potential multiple organs dysfunction. SARS-CoV-2 infection is closely related to the innate immune system and adaptive immune system. Dendritic cells (DCs), as a "bridge" connecting innate immunity and adaptive immunity, play many important roles in viral diseases. In this review, we will pay special attention to the possible mechanism of dendritic cells in human viral transmission and clinical progression of diseases, as well as the reduction and dysfunction of DCs in severe SARS-CoV-2 infection, so as to understand the mechanism and immunological characteristics of SARS-CoV-2 infection.
Topics: Humans; COVID-19; SARS-CoV-2; Cytokines; Immunity, Innate; Dendritic Cells
PubMed: 36946172
DOI: 10.1080/22221751.2023.2195019 -
Frontiers in Immunology 2023Glioblastoma is an aggressive primary brain tumor that has seen few advances in treatments for over 20 years. In response to this desperate clinical need, multiple... (Review)
Review
Glioblastoma is an aggressive primary brain tumor that has seen few advances in treatments for over 20 years. In response to this desperate clinical need, multiple immunotherapy strategies are under development, including CAR-T cells, immune checkpoint inhibitors, oncolytic viruses and dendritic cell vaccines, although these approaches are yet to yield significant clinical benefit. Potential reasons for the lack of success so far include the immunosuppressive tumor microenvironment, the blood-brain barrier, and systemic changes to the immune system driven by both the tumor and its treatment. Furthermore, while T cells are essential effector cells for tumor control, dendritic cells play an equally important role in T cell activation, and emerging evidence suggests the dendritic cell compartment may be deeply compromised in glioblastoma patients. In this review, we describe the immunotherapy approaches currently under development for glioblastoma and the challenges faced, with a particular emphasis on the critical role of the dendritic cell-T cell axis. We suggest a number of strategies that could be used to boost dendritic cell number and function and propose that the use of these in combination with T cell-targeting strategies could lead to successful tumor control.
Topics: Humans; Glioblastoma; T-Lymphocytes; Immunotherapy; Oncolytic Viruses; Dendritic Cells; Tumor Microenvironment
PubMed: 37928547
DOI: 10.3389/fimmu.2023.1261257 -
Kidney International Sep 2023Ischemia reperfusion injury is a common precipitant of acute kidney injury that occurs following disrupted perfusion to the kidney. This includes blood loss and...
Ischemia reperfusion injury is a common precipitant of acute kidney injury that occurs following disrupted perfusion to the kidney. This includes blood loss and hemodynamic shock, as well as during retrieval for deceased donor kidney transplantation. Acute kidney injury is associated with adverse long-term clinical outcomes and requires effective interventions that can modify the disease process. Immunomodulatory cell therapies such as tolerogenic dendritic cells remain a promising tool, and here we tested the hypothesis that adoptively transferred tolerogenic dendritic cells can limit kidney injury. The phenotypic and genomic signatures of bone marrow-derived syngeneic or allogeneic, Vitamin-D3/IL-10-conditioned tolerogenic dendritic cells were assessed. These cells were characterized by high PD-L1:CD86, elevated IL-10, restricted IL-12p70 secretion and a suppressed transcriptomic inflammatory profile. When infused systemically, these cells successfully abrogated kidney injury without modifying infiltrating inflammatory cell populations. They also provided protection against ischemia reperfusion injury in mice pre-treated with liposomal clodronate, suggesting the process was regulated by live, rather than reprocessed cells. Co-culture experiments and spatial transcriptomic analysis confirmed reduced kidney tubular epithelial cell injury. Thus, our data provide strong evidence that peri-operatively administered tolerogenic dendritic cells have the ability to protect against acute kidney injury and warrants further exploration as a therapeutic option. This technology may provide a clinical advantage for bench-to-bedside translation to affect patient outcomes.
Topics: Mice; Animals; Interleukin-10; Acute Kidney Injury; Kidney; Dendritic Cells; Reperfusion Injury
PubMed: 37244471
DOI: 10.1016/j.kint.2023.05.008 -
Molecular Immunology Jul 2023Since their discovery, the identity of plasmacytoid dendritic cells (pDCs) has been at the center of a continuous dispute in the field, and their classification as... (Review)
Review
Since their discovery, the identity of plasmacytoid dendritic cells (pDCs) has been at the center of a continuous dispute in the field, and their classification as dendritic cells (DCs) has been recently re-challenged. pDCs are different enough from the rest of the DC family members to be considered a lineage of cells on their own. Unlike the exclusive myeloid ontogeny of cDCs, pDCs may have dual origin developing from myeloid and lymphoid progenitors. Moreover, pDCs have the unique ability to quickly secrete abundant levels of type I interferon (IFN-I) in response to viral infections. In addition, pDCs undergo a differentiation process after pathogen recognition that allows them to activate T cells, a feature that has been shown to be independent of presumed contaminating cells. Here, we aim to provide an overview of the historic and current understanding of pDCs and argue that their classification as either lymphoid or myeloid may be an oversimplification. Instead, we propose that the capacity of pDCs to link the innate and adaptive immune response by directly sensing pathogens and activating adaptive immune responses justify their inclusion within the DC network.
Topics: Adaptive Immunity; Cell Differentiation; Dendritic Cells; Immunity, Humoral; T-Lymphocytes
PubMed: 37269733
DOI: 10.1016/j.molimm.2023.05.007 -
Nature Immunology Mar 2024Conventional dendritic cells (cDCs) include functionally and phenotypically diverse populations, such as cDC1s and cDC2s. The latter population has been variously...
Conventional dendritic cells (cDCs) include functionally and phenotypically diverse populations, such as cDC1s and cDC2s. The latter population has been variously subdivided into Notch-dependent cDC2s, KLF4-dependent cDC2s, T-bet cDC2As and T-bet cDC2Bs, but it is unclear how all these subtypes are interrelated and to what degree they represent cell states or cell subsets. All cDCs are derived from bone marrow progenitors called pre-cDCs, which circulate through the blood to colonize peripheral tissues. Here, we identified distinct mouse pre-cDC2 subsets biased to give rise to cDC2As or cDC2Bs. We showed that a Siglec-H pre-cDC2A population in the bone marrow preferentially gave rise to Siglec-H CD8α pre-cDC2As in tissues, which differentiated into T-bet cDC2As. In contrast, a Siglec-H fraction of pre-cDCs in the bone marrow and periphery mostly generated T-bet cDC2Bs, a lineage marked by the expression of LysM. Our results showed that cDC2A versus cDC2B fate specification starts in the bone marrow and suggest that cDC2 subsets are ontogenetically determined lineages, rather than cell states imposed by the peripheral tissue environment.
Topics: Animals; Mice; Cell Differentiation; Dendritic Cells; Sialic Acid Binding Immunoglobulin-like Lectins
PubMed: 38351322
DOI: 10.1038/s41590-024-01745-9