Interaction of T cell with antigen-bearing dendritic cells (DC) results in T cell activation, but whether this interaction has physiological consequences on DC function is largely unexplored. Here we ...show that when antigen-bearing DCs contact T cells, DCs initiate anti-pathogenic programs. Signals of this interaction are transmitted from the T cell to the DC, through extracellular vesicles (EV) that contain genomic and mitochondrial DNA, to induce antiviral responses via the cGAS/STING cytosolic DNA-sensing pathway and expression of IRF3-dependent interferon regulated genes. Moreover, EV-treated DCs are more resistant to subsequent viral infections. In summary, our results show that T cells prime DCs through the transfer of exosomal DNA, supporting a specific role for antigen-dependent contacts in conferring protection to DCs against pathogen infection. The reciprocal communication between innate and adaptive immune cells thus allow efficacious responses to unknown threats.
Targeted immunomodulation of dendritic cells (DCs) in vivo will enable manipulation of T-cell priming and amplification of anticancer immune responses, but a general strategy has been lacking. Here ...we show that DCs concentrated by a biomaterial can be metabolically labelled with azido groups in situ, which allows for their subsequent tracking and targeted modulation over time. Azido-labelled DCs were detected in lymph nodes for weeks, and could covalently capture dibenzocyclooctyne (DBCO)-bearing antigens and adjuvants via efficient Click chemistry for improved antigen-specific CD8
T-cell responses and antitumour efficacy. We also show that azido labelling of DCs allowed for in vitro and in vivo conjugation of DBCO-modified cytokines, including DBCO-IL-15/IL-15Rα, to improve priming of antigen-specific CD8
T cells. This DC labelling and targeted modulation technology provides an unprecedented strategy for manipulating DCs and regulating DC-T-cell interactions in vivo.
Dendritic cell subsets Macri, Christophe; Pang, Ee Shan; Patton, Timothy ...
Seminars in cell & developmental biology,
December 2018, 2018-12-00, 20181201, Letnik:
84
Journal Article
Recenzirano
Dendritic cells (DC) are professional antigen presenting cells comprising a variety of subsets, as either resident or migrating cells, in lymphoid and non-lymphoid organs.
In the steady state DC ...continually process and present antigens on MHCI and MHCII, processes that are highly upregulated upon activation. By expressing differential sets of pattern recognition receptors different DC subsets are able to respond to a range of pathogenic and danger stimuli, enabling functional specialisation of the DC. The knowledge of functional specialisation of DC subsets is key to efficient priming of T cells, to the design of effective vaccine adjuvants and to understanding the role of different DC in health and disease. This review outlines mouse and human steady state DC subsets and key attributes that define their distinct functions.
The formation of mammalian dendritic cells (DCs) is controlled by multiple hematopoietic transcription factors, including IRF8. Loss of IRF8 exerts a differential effect on DC subsets, including ...plasmacytoid DCs (pDCs) and the classical DC lineages cDC1 and cDC2. In humans, cDC2-related subsets have been described including AXL+SIGLEC6+ pre-DC, DC2 and DC3. The origin of this heterogeneity is unknown. Using high-dimensional analysis, in vitro differentiation, and an allelic series of human IRF8 deficiency, we demonstrated that cDC2 (CD1c+DC) heterogeneity originates from two distinct pathways of development. The lymphoid-primed IRF8hi pathway, marked by CD123 and BTLA, carried pDC, cDC1, and DC2 trajectories, while the common myeloid IRF8lo pathway, expressing SIRPA, formed DC3s and monocytes. We traced distinct trajectories through the granulocyte-macrophage progenitor (GMP) compartment showing that AXL+SIGLEC6+ pre-DCs mapped exclusively to the DC2 pathway. In keeping with their lower requirement for IRF8, DC3s expand to replace DC2s in human partial IRF8 deficiency.
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•Distinct development trajectories of DC2 and DC3 underpin human cDC2 heterogeneity•pDC, cDC1, and DC2 (classical DCs) develop from LMPPs along a CD123+ IRF8high pathway•DC3 and monocytes develop from CD33+ GMPs along an IRF8low SIRPA+ pathway•IRF8 deficiency causes gene dose-dependent loss of IRF8high then IRF8low pathway DCs
Heterogeneity of human CD1c+ dendritic cells (cDC2s) is described, but how this arises is unknown. Cytlak and colleagues demonstrate that the cDC2 subsets, DC2 and DC3, develop along distinct hematopoietic trajectories, defined by differential IRF8 expression. DC2s develop from LMPPs along an IRF8hi pathway, while DC3 differentiation follows an IRF8low trajectory.
Dendritic cells (DCs), the most efficient antigen-presenting cells, are necessary for the effective activation of naïve T cells. DCs can also acquire tolerogenic functions in vivo and in vitro in ...response to various stimuli, including interleukin (IL)-10, transforming growth factor (TGF)-β, vitamin D3, corticosteroids, and rapamycin. In this review, we provide a wide perspective on the regulatory mechanisms, including crosstalk with other cell types, downstream signaling pathways, transcription factors, and epigenetics, underlying the acquisition of tolerogenesis by DCs, with a special focus on human studies. Finally, we present clinical assays targeting, or based on, tolerogenic DCs in inflammatory diseases. Our discussion provides a useful resource for better understanding the biology of tolerogenic DCs and their manipulation to improve the immunological fitness of patients with certain inflammatory conditions.
Dendritic cells (DCs) play various roles as antigen-presenting cells and participate in central and peripheral tolerance. Recent single-cell studies are redefining and expanding their classification and roles.Inflammatory dendritic cells (infDCs), derived from monocytes, play a relevant role in the course of autoimmune diseases. In vitro monocyte-derived DCs can be used in studies analyzing tolerance-inducing agents and potential therapeutics.Transcription factor-mediated and epigenetic mechanisms involved in the tolerogenic differentiation of DCs are being elucidated. DNA methylation both in vivo and in vitro has arisen as a relevant molecular mechanism in tolerogenic DC (tolDC) differentiation.TolDCs can promote tolerance towards different immune cell types involved in autoimmunity via contact-dependent interactions and by secreting pleiotropic cytokines and metabolites.Therapies centered on the administration of tolDCs are yielding promising results as alternatives to immunomodulators for certain chronic inflammatory diseases and organ transplantation, given their ability to specifically suppress autoimmune responses without inducing general immunosuppression.
We assessed gene expression in tissue macrophages from various mouse organs. The diversity in gene expression among different populations of macrophages was considerable. Only a few hundred mRNA ...transcripts were selectively expressed by macrophages rather than dendritic cells, and many of these were not present in all macrophages. Nonetheless, well-characterized surface markers, including MerTK and FcγR1 (CD64), along with a cluster of previously unidentified transcripts, were distinctly and universally associated with mature tissue macrophages. TCEF3, C/EBP-α, Bach1 and CREG-1 were among the transcriptional regulators predicted to regulate these core macrophage-associated genes. The mRNA encoding other transcription factors, such as Gata6, was associated with single macrophage populations. We further identified how these transcripts and the proteins they encode facilitated distinguishing macrophages from dendritic cells.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Stromal cells (SCs) establish the compartmentalization of lymphoid tissues critical to the immune response. However, the full diversity of lymph node (LN) SCs remains undefined. Using droplet-based ...single-cell RNA sequencing, we identified nine peripheral LN non-endothelial SC clusters. Included are the established subsets, Ccl19hi T-zone reticular cells (TRCs), marginal reticular cells, follicular dendritic cells (FDCs), and perivascular cells. We also identified Ccl19lo TRCs, likely including cholesterol-25-hydroxylase+ cells located at the T-zone perimeter, Cxcl9+ TRCs in the T-zone and interfollicular region, CD34+ SCs in the capsule and medullary vessel adventitia, indolethylamine N-methyltransferase+ SCs in the medullary cords, and Nr4a1+ SCs in several niches. These data help define how transcriptionally distinct LN SCs support niche-restricted immune functions and provide evidence that many SCs are in an activated state.
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•Single-cell RNA sequencing of lymph node stromal cells reveals nine clusters•Known subsets TRCs, MRCs, FDCs, and perivascular cells identified•Five additional stromal cell clusters identified and anatomical locations determined•Two clusters, Cxcl9+ TRCs and Nr4a1+ SCs, are defined by activation signatures
Lymph node stromal cells support diverse processes, but bulk assessments obscure their niche-specific functions. Rodda et al. identify transcriptional profiles for nine lymph node stromal cell clusters using single-cell RNA sequencing, validate subset markers in situ, and suggest niche-restricted functions.
Summary Checkpoint blockade immunotherapy has received mainstream attention as a result of striking and durable clinical responses in some patients with metastatic disease and a reasonable response ...rate in many tumour types. The activity of checkpoint blockade immunotherapy is not restricted to melanoma or lung cancer, and additional indications are expected in the future, with responses already reported in renal cancer, bladder cancer, and Hodgkin's lymphoma among many others. Additionally, the interactions between radiation and the immune system have been investigated, with several studies describing the synergistic effects on local and distant tumour control when radiation therapy is combined with immunotherapy. Clinical enthusiasm for this approach is strengthened by the many ongoing trials combining immunotherapy with definitive and palliative radiation. Herein, we discuss the biological and mechanistic rationale behind combining radiation with checkpoint blockade immunotherapy, with a focus on the preclinical data supporting this potentially synergistic combination. We explore potential hypotheses and important considerations for clinical trial designs. Finally, we reintroduce the notion of radiosensitising immunotherapy, akin to radiosensitising chemotherapy, as a potential definitive therapeutic modality.
Abstract
Studies of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)–infected patients and experimentally infected animals indicate a critical role for augmented expression of ...proinflammatory chemokines and cytokines in severe disease. Here, we demonstrate that SARS-CoV-2 infection of human monocyte-derived macrophages (MDMs) and monocyte-derived dendritic cells was abortive, but induced the production of multiple antiviral and proinflammatory cytokines (interferon-α, interferon-β, tumor necrosis factor, and interleukins 1β, 6, and 10) and a chemokine (CXCL10). Despite the lack of efficient replication in MDMs, SARS-CoV-2 induced profound interferon-mediated cell death of host cells. Macrophage activation and death were not enhanced by exposure to low levels of convalescent plasma, suggesting that antibody-dependent enhancement of infection does not contribute to cell death. Together, these results indicate that infection of macrophages and dendritic cells potentially plays a major role in coronavirus disease 2019 pathogenesis, even in the absence of productive infection.
Severe acute respiratory syndrome coronavirus 2 exhibited angiotensin converting enzyme 2 dependent abortive infection of human myeloid cells. The infection induced expression of antiviral and proinflammatory cytokines and chemokines, which ultimately resulted in type I interferon-mediated cell death of human macrophages.
Graphical Abstract
Atherosclerosis is a complex chronic disease. The accumulation of myeloid cells in the arterial intima, including macrophages and dendritic cells (DCs), is a feature of early stages of disease. For ...decades, it has been known that monocyte recruitment to the intima contributes to the burden of lesion macrophages. Yet, this paradigm may require reevaluation in light of recent advances in understanding of tissue macrophage ontogeny, their capacity for self-renewal, as well as observations that macrophages proliferate throughout atherogenesis and that self-renewal is critical for maintenance of macrophages in advanced lesions. The rate of atherosclerotic lesion formation is profoundly influenced by innate and adaptive immunity, which can be regulated locally within atherosclerotic lesions, as well as in secondary lymphoid organs, the bone marrow and the blood. DCs are important modulators of immunity. Advances in the past decade have cemented our understanding of DC subsets, functions, hematopoietic origin, gene expression patterns, transcription factors critical for differentiation, and provided new tools for study of DC biology. The functions of macrophages and DCs overlap to some extent, thus it is important to reassess the contributions of each of these myeloid cells taking into account strict criteria of cell identification, ontogeny, and determine whether their key roles are within atherosclerotic lesions or secondary lymphoid organs. This review will highlight key aspect of macrophage and DC biology, summarize how these cells participate in different stages of atherogenesis and comment on complexities, controversies, and gaps in knowledge in the field.
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