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Immunity Aug 2023Conventional dendritic cells (cDCs) are professional antigen-presenting cells that control the adaptive immune response. Their subsets and developmental origins have...
Conventional dendritic cells (cDCs) are professional antigen-presenting cells that control the adaptive immune response. Their subsets and developmental origins have been intensively investigated but are still not fully understood as their phenotypes, especially in the DC2 lineage and the recently described human DC3s, overlap with monocytes. Here, using LEGENDScreen to profile DC vs. monocyte lineages, we found sustained expression of FLT3 and CD45RB through the whole DC lineage, allowing DCs and their precursors to be distinguished from monocytes. Using fate mapping models, single-cell RNA sequencing and adoptive transfer, we identified a lineage of murine CD16/32CD172a DC3, distinct from DC2, arising from Ly6C monocyte-DC progenitors (MDPs) through Lyz2Ly6CCD11c pro-DC3s, whereas DC2s develop from common DC progenitors (CDPs) through CD7Ly6CCD11c pre-DC2s. Corresponding DC subsets, developmental stages, and lineages exist in humans. These findings reveal DC3 as a DC lineage phenotypically related to but developmentally different from monocytes and DC2s.
Topics: Mice; Humans; Animals; Monocytes; Stem Cells; Phenotype; Cells, Cultured; Dendritic Cells; Cell Differentiation
PubMed: 37506694
DOI: 10.1016/j.immuni.2023.07.001 -
Cellular & Molecular Immunology May 2023Dendritic cells (DCs) exhibit a specialized antigen-presenting function and play crucial roles in both innate and adaptive immune responses. Due to their ability to... (Review)
Review
Dendritic cells (DCs) exhibit a specialized antigen-presenting function and play crucial roles in both innate and adaptive immune responses. Due to their ability to cross-present tumor cell-associated antigens to naïve T cells, DCs are instrumental in the generation of specific T-cell-mediated antitumor effector responses in the control of tumor growth and tumor cell dissemination. Within an immunosuppressive tumor microenvironment, DC antitumor functions can, however, be severely impaired. In this review, we focus on the mechanisms of DC capture and activation by tumor cell antigens and the role of the tumor microenvironment in shaping DC functions, taking advantage of recent studies showing the phenotype acquisition, transcriptional state and functional programs revealed by scRNA-seq analysis. The therapeutic potential of DC-mediated tumor antigen sensing in priming antitumor immunity is also discussed.
Topics: Humans; Dendritic Cells; Neoplasms; Antigens, Neoplasm; T-Lymphocytes; Tumor Microenvironment
PubMed: 36949244
DOI: 10.1038/s41423-023-00990-6 -
Annual Review of Immunology Apr 2021As the professional antigen-presenting cells of the immune system, dendritic cells (DCs) sense the microenvironment and shape the ensuing adaptive immune response. DCs... (Review)
Review
As the professional antigen-presenting cells of the immune system, dendritic cells (DCs) sense the microenvironment and shape the ensuing adaptive immune response. DCs can induce both immune activation and immune tolerance according to the peripheral cues. Recent work has established that DCs comprise several phenotypically and functionally heterogeneous subsets that differentially regulate T lymphocyte differentiation. This review summarizes both mouse and human DC subset phenotypes, development, diversification, and function. We focus on advances in our understanding of how different DC subsets regulate distinct CD4 T helper (Th) cell differentiation outcomes, including Th1, Th2, Th17, T follicular helper, and T regulatory cells. We review DC subset intrinsic properties, local tissue microenvironments, and other immune cells that together determine Th cell differentiation during homeostasis and inflammation.
Topics: Animals; Dendritic Cells; Humans; Immune Tolerance; Lymphocyte Activation; Mice; T-Lymphocytes, Regulatory; Th17 Cells
PubMed: 33710920
DOI: 10.1146/annurev-immunol-101819-025146 -
Science Immunology Apr 2022Dendritic cells (DCs) are professional antigen-presenting cells, orchestrating innate and adaptive immunity during infections, autoimmune diseases, and malignancies.... (Review)
Review
Dendritic cells (DCs) are professional antigen-presenting cells, orchestrating innate and adaptive immunity during infections, autoimmune diseases, and malignancies. Since the discovery of DCs almost 50 years ago, our understanding of their biology in humans has increased substantially. Here, we review both antitumor and tolerogenic DC responses in cancer and discuss lineage-specific contributions by their functionally specialized subsets, including the conventional DC (cDC) subsets cDC1 and cDC2, the newly described DC3, and the plasmacytoid DCs (pDCs), focusing on the human setting. In addition, we review the lineage-unrestricted "mature DCs enriched in immunoregulatory molecules" (mregDC) state recently described across different human tumors.
Topics: Adaptive Immunity; Dendritic Cells; Humans; Neoplasms
PubMed: 35363544
DOI: 10.1126/sciimmunol.abm9409 -
Annual Review of Virology Sep 2019More than 80 different adenovirus (AdV) types infect humans through the respiratory, ocular, or gastrointestinal tracts. They cause acute clinical mani-festations or... (Review)
Review
More than 80 different adenovirus (AdV) types infect humans through the respiratory, ocular, or gastrointestinal tracts. They cause acute clinical mani-festations or persist under humoral and cell-based immunity. Immuno-suppressed individuals are at risk of death from an AdV infection. Concepts about cell entry of AdV build on strong foundations from molecular and cellular biology-and increasingly physical virology. Here, we discuss how virions enter and deliver their genome into the nucleus of epithelial cells. This process breaks open the virion at distinct sites because the particle has nonisometric mechanical strength and reacts to specific host factors along the entry pathway. We further describe how macrophages and dendritic cells resist AdV infection yet enhance productive entry into polarized epithelial cells. A deep understanding of the viral mechanisms and cell biological and biophysical principles will continue to unravel how epithelial and antigen-presenting cells respond to AdVs and control inflammation and persistence in pathology and therapy.
Topics: Adenoviridae; Adenoviridae Infections; Animals; Antigen-Presenting Cells; Dendritic Cells; Epithelial Cells; Humans; Macrophages; Mice; Virion; Virus Internalization; Virus Replication
PubMed: 31283442
DOI: 10.1146/annurev-virology-092818-015550 -
Journal of the National Comprehensive... May 2023Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematologic malignancy with an aggressive clinical course and poor prognosis. BPDCN is most often... (Review)
Review
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematologic malignancy with an aggressive clinical course and poor prognosis. BPDCN is most often characterized by its presentation with distinct cutaneous lesions. Bone marrow involvement, lymphadenopathy, splenomegaly, and/or cytopenias are also seen to varying degrees. BPDCN presents with diffuse, monomorphous blasts with irregular nuclei, fine chromatin, and scant, agranular cytoplasm. Expression of CD4, CD56, and CD123 is the hallmark of BPDCN. The presence of ≥4 of CD4, CD56, CD123, TCL1, TCF4, and CD303 is necessary for the diagnosis of BPDCN. Prior to December 2018, management of BPDCN revolved around intensive chemotherapy using acute myeloid leukemia or acute lymphoblastic leukemia regimens. However, responses were transient with poor overall survival (OS). Allogeneic stem cell transplantation (alloSCT) is the only potentially curative treatment for BPDCN. Even so, only a minority of patients are candidates for alloSCT given the preponderance of disease in older individuals. For the few fit patients who are candidates for alloSCT, the aim is to achieve complete remission prior to alloSCT. Tagraxofusp (SL-401), a recombinant fusion protein containing interleukin-3 fused to truncated diphtheria toxin, was the first approved CD123-targeted therapy for BPDCN based on a phase I/II clinical trial showing a 90% overall response rate. It was approved by the FDA on December 21, 2018. Capillary leak syndrome is an important adverse effect of tagraxofusp that requires close monitoring. Several clinical trials are underway to study other regimens for the treatment of BPDCN, including IMGN632 (pivekimab sunirine), venetoclax (alone and in combination with hypomethylating agents), CAR-T cells, and bispecific monoclonal antibodies.
Topics: Humans; Aged; Interleukin-3 Receptor alpha Subunit; Dendritic Cells; Hematopoietic Stem Cell Transplantation; Myeloproliferative Disorders; Hematologic Neoplasms; Skin Neoplasms
PubMed: 37156483
DOI: 10.6004/jnccn.2023.7026 -
Frontiers in Immunology 2020Despite significant advances in the field of cancer immunotherapy, the majority of patients still do not benefit from treatment and must rely on traditional therapies.... (Review)
Review
Despite significant advances in the field of cancer immunotherapy, the majority of patients still do not benefit from treatment and must rely on traditional therapies. Dendritic cells have long been a focus of cancer immunotherapy due to their role in inducing protective adaptive immunity, but cancer vaccines have shown limited efficacy in the past. With the advent of immune checkpoint blockade and the ability to identify patient-specific neoantigens, new vaccines, and combinatorial therapies are being evaluated in the clinic. Dendritic cells are also emerging as critical regulators of the immune response within tumors. Understanding how to augment the function of these intratumoral dendritic cells could offer new approaches to enhance immunotherapy, in addition to improving the cytotoxic and targeted therapies that are partially dependent upon a robust immune response for their efficacy. Here we will discuss the role of specific dendritic cell subsets in regulating the anti-tumor immune response, as well as the current status of dendritic cell-based immunotherapies, in order to provide an overview for future lines of research and clinical trials.
Topics: Animals; Antineoplastic Agents, Immunological; Cancer Vaccines; Dendritic Cells; Humans; Immune Checkpoint Inhibitors; Immunotherapy, Adoptive; Neoplasms; Phenotype; Signal Transduction; Treatment Outcome
PubMed: 32508825
DOI: 10.3389/fimmu.2020.00924 -
Molecular Cancer Apr 2021Synthetic mRNA provides a template for the synthesis of any given protein, protein fragment or peptide and lends itself to a broad range of pharmaceutical applications,... (Review)
Review
Synthetic mRNA provides a template for the synthesis of any given protein, protein fragment or peptide and lends itself to a broad range of pharmaceutical applications, including different modalities of cancer immunotherapy. With the ease of rapid, large scale Good Manufacturing Practice-grade mRNA production, mRNA is ideally poised not only for off-the shelf cancer vaccines but also for personalized neoantigen vaccination. The ability to stimulate pattern recognition receptors and thus an anti-viral type of innate immune response equips mRNA-based vaccines with inherent adjuvanticity. Nucleoside modification and elimination of double-stranded RNA can reduce the immunomodulatory activity of mRNA and increase and prolong protein production. In combination with nanoparticle-based formulations that increase transfection efficiency and facilitate lymphatic system targeting, nucleoside-modified mRNA enables efficient delivery of cytokines, costimulatory receptors, or therapeutic antibodies. Steady but transient production of the encoded bioactive molecule from the mRNA template can improve the pharmacokinetic, pharmacodynamic and safety properties as compared to the respective recombinant proteins. This may be harnessed for applications that benefit from a higher level of expression control, such as chimeric antigen receptor (CAR)-modified adoptive T-cell therapies. This review highlights the advancements in the field of mRNA-based cancer therapeutics, providing insights into key preclinical developments and the evolving clinical landscape.
Topics: Animals; Antibodies; Antigen Presentation; Antigen-Presenting Cells; Antigens, Neoplasm; Biomarkers, Tumor; Cancer Vaccines; Cytokines; Dendritic Cells; Genetic Therapy; Humans; Immunologic Factors; Immunotherapy; Neoplasms; RNA, Messenger; Receptors, Antigen, T-Cell; T-Lymphocytes
PubMed: 33858437
DOI: 10.1186/s12943-021-01348-0 -
Cellular & Molecular Immunology Jun 2020Dendritic cells are powerful antigen-presenting cells that are essential for the priming of T cell responses. In addition to providing T-cell-receptor ligands and... (Review)
Review
Dendritic cells are powerful antigen-presenting cells that are essential for the priming of T cell responses. In addition to providing T-cell-receptor ligands and co-stimulatory molecules for naive T cell activation and expansion, dendritic cells are thought to also provide signals for the differentiation of CD4+ T cells into effector T cell populations. The mechanisms by which dendritic cells are able to adapt and respond to the great variety of infectious stimuli they are confronted with, and prime an appropriate CD4+ T cell response, are only partly understood. It is known that in the steady-state dendritic cells are highly heterogenous both in phenotype and transcriptional profile, and that this variability is dependent on developmental lineage, maturation stage, and the tissue environment in which dendritic cells are located. Exposure to infectious agents interfaces with this pre-existing heterogeneity by providing ligands for pattern-recognition and toll-like receptors that are variably expressed on different dendritic cell subsets, and elicit production of cytokines and chemokines to support innate cell activation and drive T cell differentiation. Here we review current information on dendritic cell biology, their heterogeneity, and the properties of different dendritic cell subsets. We then consider the signals required for the development of different types of Th immune responses, and the cellular and molecular evidence implicating different subsets of dendritic cells in providing such signals. We outline how dendritic cell subsets tailor their response according to the infectious agent, and how such transcriptional plasticity enables them to drive different types of immune responses.
Topics: Animals; Antigen Presentation; Cell Differentiation; Dendritic Cells; Humans; Models, Biological; T-Lymphocytes, Helper-Inducer; Transcription, Genetic
PubMed: 32433540
DOI: 10.1038/s41423-020-0465-0 -
Nature Oct 2022Establishing and maintaining tolerance to self-antigens or innocuous foreign antigens is vital for the preservation of organismal health. Within the thymus, medullary...
Establishing and maintaining tolerance to self-antigens or innocuous foreign antigens is vital for the preservation of organismal health. Within the thymus, medullary thymic epithelial cells (mTECs) expressing autoimmune regulator (AIRE) have a critical role in self-tolerance through deletion of autoreactive T cells and promotion of thymic regulatory T (T) cell development. Within weeks of birth, a separate wave of T cell differentiation occurs in the periphery upon exposure to antigens derived from the diet and commensal microbiota, yet the cell types responsible for the generation of peripheral T (pT) cells have not been identified. Here we describe the identification of a class of RORγt antigen-presenting cells called Thetis cells, with transcriptional features of both mTECs and dendritic cells, comprising four major sub-groups (TC I-TC IV). We uncover a developmental wave of Thetis cells within intestinal lymph nodes during a critical window in early life, coinciding with the wave of pT cell differentiation. Whereas TC I and TC III expressed the signature mTEC nuclear factor AIRE, TC IV lacked AIRE expression and was enriched for molecules required for pT generation, including the TGF-β-activating integrin αvβ8. Loss of either major histocompatibility complex class II (MHCII) or ITGB8 by Thetis cells led to a profound impairment in intestinal pT differentiation, with ensuing colitis. By contrast, MHCII expression by RORγt group 3 innate lymphoid cells (ILC3) and classical dendritic cells was neither sufficient nor required for pT generation, further implicating TC IV as the tolerogenic RORγt antigen-presenting cell with an essential function in early life. Our studies reveal parallel pathways for the establishment of tolerance to self and foreign antigens in the thymus and periphery, respectively, marked by the involvement of shared cellular and transcriptional programmes.
Topics: Cell Differentiation; Dendritic Cells; Epithelial Cells; Gastrointestinal Microbiome; Immunity, Innate; Nuclear Receptor Subfamily 1, Group F, Member 3; Thymus Gland; Transforming Growth Factor beta; Antigen-Presenting Cells; T-Lymphocytes, Regulatory; Immune Tolerance; Lymph Nodes
PubMed: 36070798
DOI: 10.1038/s41586-022-05309-5