scholarly journals Cancer Acidity and Hypertonicity Contribute to Dysfunction of Tumor-Associated Dendritic Cells: Potential Impact on Antigen Cross-Presentation Machinery

Cancers ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 2403
Author(s):  
Sven Burgdorf ◽  
Stefan Porubsky ◽  
Alexander Marx ◽  
Zoran V. Popovic
Keyword(s):  
Dendritic Cells ◽  
Immune Escape ◽  
Cell Types ◽  
Mononuclear Phagocyte ◽  
Scientific Data ◽  
Neoplastic Tissue ◽  
Antigen Uptake ◽  
Mhc I ◽  
Cross Presentation ◽  
Extracellular Matrix Components

Macrophages (MΦ) and dendritic cells (DC), major players of the mononuclear phagocyte system (MoPh), are potent antigen presenting cells that steadily sense and respond to signals from the surrounding microenvironment, leading to either immunogenic or tolerogenic outcomes. Next to classical MHC-I/MHC-II antigen-presentation pathways described in the vast majority of cell types, a subset of MoPh (CD8+, XCR1+, CLEC9A+, BDCA3+ conventional DCs in human) is endowed with a high competence to cross-present external (engulfed) antigens on MHC-I molecules to CD8+ T-cells. This exceptional DC function is thought to be a crucial crossroad in cytotoxic antitumor immunity and has been extensively studied in the past decades. Biophysical and biochemical fingerprints of tumor micromilieus show significant spatiotemporal differences in comparison to non-neoplastic tissue. In tumors, low pH (mainly due to extracellular lactate accumulation via the Warburg effect and via glutaminolysis) and high oncotic and osmotic pressure (resulting from tumor debris, increased extracellular matrix components but in part also triggered by nutritive aspects) are—despite fluctuations and difficulties in measurement—likely the most constant general hallmarks of tumor microenvironment. Here, we focus on the influence of acidic and hypertonic micromilieu on the capacity of DCs to cross-present tumor-specific antigens. We discuss complex and in part controversial scientific data on the interference of these factors with to date reported mechanisms of antigen uptake, processing and cross-presentation, and we highlight their potential role in cancer immune escape and poor clinical response to DC vaccines.

scholarly journals Myeloid and Plasmacytoid Dendritic Cells and Cancer – New Insights

2019 ◽  
Vol 7 (19) ◽  
pp. 3324-3340 ◽  
Author(s):  
Maya Gulubova ◽  
Koni Vancho Ivanova ◽  
Mehmed Hadzhi ◽  
Dimitur Chonov ◽  
Maria Magdalena Ignatova ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Immune Responses ◽  
Cell Types ◽  
Tumour Microenvironment ◽  
Mhc I ◽  
Cross Presentation ◽  
Adaptive Immune ◽  
Histocompatibility Complex ◽  
T Helpers

Dendritic cells (DCs) use effective mechanisms to combat antigens and to bring about adaptive immune responses through their ability to stimulate nӓive T cells. At present, four major cell types are categorised as DCs: Classical or conventional (cDCs), Plasmacytoid (pDCs), Langerhans cells (LCs), and monocyte-derived DCs (Mo-DCs). It was suggested that pDCs, CD1c+ DCs and CD141+ DCs in humans are equivalent to mouse pDCs, CD11b+ DCs and CD8α+ DCs, respectively. Human CD141+ DCs compared to mouse CD8α+ DCs have remarkable functional and transcriptomic similarities. Characteristic markers, transcription factors, toll-like receptors, T helpers (Th) polarisation, cytokines, etc. of DCs are discussed in this review. Major histocompatibility complex (MHC) I and II antigen presentation, cross-presentation and Th polarisation are defined, and the dual role of DCs in the tumour is discussed. Human DCs are the main immune cells that orchestrate the immune response in the tumour microenvironment.

scholarly journals Distinct antigen uptake receptors route to the same storage compartments for cross‐presentation in dendritic cells

Immunology ◽  
2021 ◽  
Author(s):  
Nataschja I. Ho ◽  
Marcel G. Camps ◽  
Juan J. Garcia‐Vallejo ◽  
Erik Bos ◽  
Abraham J. Koster ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Antigen Uptake ◽  
Cross Presentation

scholarly journals Transcriptional network analysis of transcriptomic diversity in resident tissue macrophages and dendritic cells in the mouse mononuclear phagocyte system

2020 ◽  
Author(s):  
Kim M. Summers ◽  
Stephen J. Bush ◽  
David A. Hume
Keyword(s):  
Dendritic Cells ◽  
Network Analysis ◽  
Single Cell ◽  
Cell Types ◽  
Mononuclear Phagocyte ◽  
The Body ◽  
Mononuclear Phagocyte System ◽  
Primary Data ◽  
Analysis Tool ◽  
Rna Seq

AbstractThe mononuclear phagocyte system (MPS) is a family of cells including progenitors, circulating blood monocytes, resident tissue macrophages and dendritic cells (DC) present in every tissue in the body. To test the relationships between markers and transcriptomic diversity in the MPS, we collected from NCBI-GEO >500 quality RNA-seq datasets generated from mouse MPS cells isolated from multiple tissues. The primary data were randomly down-sized to a depth of 10 million reads and requantified. The resulting dataset was clustered using the network analysis tool Graphia. A sample-to-sample matrix revealed that MPS populations could be separated based upon tissue of origin. Cells identified as classical DC subsets, cDC1 and cDC2, and lacking Fcgr1 (CD64), were centrally-located within the MPS cluster and no more distinct than other MPS cell types. A gene-to-gene correlation matrix identified large generic co-expression clusters associated with MPS maturation and innate immune function. Smaller co-expression gene clusters including the transcription factors that drive them showed higher expression within defined isolated cells, including macrophages and DC from specific tissues. They include a cluster containing Lyve1 that implies a function in endothelial cell homeostasis, a cluster of transcripts enriched in intestinal macrophages and a generic cDC cluster associated with Ccr7. However, transcripts encoding many other putative MPS subset markers including Adgre1, Itgax, Itgam, Clec9a, Cd163, Mertk, Retnla and H2-a/e (class II MHC) clustered idiosyncratically and were not correlated with underlying functions. The data provide no support for the concept of markers of M2 polarization or the specific adaptation of DC to present antigen to T cells. Co-expression of immediate early genes (e.g. Egr1, Fos, Dusp1) and inflammatory cytokines and chemokines (Tnf, Il1b, Ccl3/4) indicated that all tissue disaggregation protocols activate MPS cells. Tissue-specific expression clusters indicated that all cell isolation procedures also co-purify other unrelated cell types that may interact with MPS cells in vivo. Comparative analysis of public RNA-seq and single cell RNA-seq data from the same lung cell populations showed that the extensive heterogeneity implied by the global cluster analysis may be even greater at a single cell level with few markers strongly correlated with each other. This analysis highlights the power of large datasets to identify the diversity of MPS cellular phenotypes, and the limited predictive value of surface markers to define lineages, functions or subpopulations.

scholarly journals Genomic programming of antigen cross-presentation in IRF4-expressing human Langerhans cells

2019 ◽  
Author(s):  
Marta E Polak ◽  
Sofia Sirvent ◽  
Kalum Clayton ◽  
James Davies ◽  
Andres F. Vallejo ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Transcription Factor ◽  
Antigen Presentation ◽  
Langerhans Cells ◽  
Mhc I ◽  
Cross Presentation ◽  
Mhc Ii ◽  
T Cell Immune Responses ◽  
Dependent Protein ◽  
Chromatin Profiling

AbstractLangerhans cells (LCs) in the epidermis present MHC I and MHC II-restricted antigens thereby priming either CD8 or CD4 T cell immune responses. The genomic programs and transcription factors regulating antigen presentation in LCs remain to be elucidated. We show human LCs are highly efficient in MHC I-antigen cross-presentation but lack the transcription factor IRF8 that is critical in dendritic cells. LC migration from the epidermis enhances their ability to cross-present antigens and is accompanied by the induction of the transcription factor IRF4, whose expression is correlated by scRNA-seq with genes involved in ubiquitin-dependent protein degradation. Chromatin profiling reveals enrichment of EICE and AICE composite DNA binding motifs in regulatory regions of antigen-presentation genes, which can be recognized by IRF4 in conjunction with PU.1 or BATF3 expressed in LCs. Thus, the genomic programming of human LCs including inducible expression of IRF4 with enhanced cross-presentation distinguishes them from conventional dendritic cells.

scholarly journals Non-canonical autophagy in dendritic cells restricts cross-presentation and anti-tumor immunity

2019 ◽  
Author(s):  
Payel Sil ◽  
Fei Zhao ◽  
Ginger W. Muse ◽  
Sing-Wai Wong ◽  
Joseph P. Kolb ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Molecular Mechanisms ◽  
Tumor Therapy ◽  
Tumor Burden ◽  
Mhc I ◽  
Cross Presentation ◽  
Cell Responses ◽  
Histocompatibility Complex ◽  
Novel Strategy ◽  
Gain Access

SummaryMajor Histocompatibility Complex I (MHC-I) molecules classically present peptides derived from endogenous antigens, but exogenous antigens can also gain access to the MHC-I machinery in dendritic cells (DCs), which can activate antigen-specific CD8+T cells. This process, termed cross-presentation, can be triggered by the uptake of dying autologous cells, including tumor cells, by DCs. The molecular mechanisms that underlie efficient cross-presentation remain largely uncharacterized, and an improved understanding of these mechanisms might reveal novel strategies for anti-tumor therapies. Rubicon (RUBCN) is a molecule required for LC3-associated phagocytosis (LAP), but dispensable for canonical autophagy, and mice lacking this protein develop an autoimmune inflammatory pathology with age. Here, we demonstrate thatRubcn-deficient DCs have increased retention of engulfed cellular cargo in immature phagosomes resulting in increased phagosome-to-cytosol escape and antigen access to proteasome-mediated degradation. As a result, mice selectively lackingRubcnin DCs mount stronger tumor antigen-specific CD8+T cell responses and exhibit decreased tumor burden compared to wild type littermates. These findings identify LAP as a key regulator of cross-presentation and suggest that targeting RUBCN might represent a novel strategy for anti-tumor therapy.

Elucidating Molecular Mechanisms of Cross-Presentation

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2217-2217
Author(s):  
Shin-Rong Julia Wu
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Immune System ◽  
Molecular Mechanisms ◽  
Conflicts Of Interest ◽  
Activation Markers ◽  
Mhc I ◽  
Cross Presentation ◽  
Intact Immune System

The immune system regulates many processes vital to homeostasis. Antigen cross-presentation, an immune process specific to dendritic cells (DCs), critically contributes to maintaining homeostasis by regulating immune tolerance, antiviral activity, and antitumor responses. Through cross-presentation, extracellular antigen is processed and presented by MHC I on DCs to CD8 T cells. Despite cross-presentation's crucial role in mediating immune responses, its molecular regulation remains poorly defined. A potential breakthrough came when, using an in vitro shRNA-mediated knockdown (KD) approach, a group identified Sec22b as a central regulatory molecule of the pathway1. They demonstrated that Sec22b mediates recruitment of proteins necessary for MHC I-antigen loading from the endoplasmic reticulum (ER)-Golgi intermediate compartment (ERGIC) to the antigen-containing phagosome, promoting cross-presentation. Thus, we tested the hypothesis that Sec22b mediates cross-presentation in vivo, in the context of an intact immune system under physiological conditions. We generated DC-specific Sec22b knockout (KO) mice (CD11cCre Sec22bfl/fl) from Sec22b-conditional gene trapped founder mice. These mice develop normally and have an intact immune system. KO DCs from spleen and bone marrow (BM) have Cre-mediated excision at the Sec22b locus, verified by PCR, and reduction of Sec22b production, verified by Western Blot. KO DCs from spleen and BM express activation markers in response to TLR and NLR stimulation at comparable levels to Cre- Sec22bfl/fl (FL) mice. By adoptively transferring ovalbumin (OVA)-specific (OT-I) T cells into these mice, then injecting with soluble OVA i.p., we measured OT-I T cell proliferation as a readout of cross-presentation. To our surprise, we saw no difference in the ability of KO versus FL mice to cross-present OVA (p >0.9). This observation was verified with in vitro assays with KO DCs from BM and spleen cross-presenting soluble OVA (0-3 mg/mL). We obtained similar findings using bead-bound, insoluble OVA. From this, we concluded Sec22b is not necessary for cross-presentation, invalidating our hypothesis. We were, however, able to reduce cross-presentation by shRNA-mediated KD of Sec22b (p <0.05), reproducing published observations. This discrepancy in observations was not due to functional compensation in KO BMDCs by Sec22b homologs, Sec22a or Sec22c, which we determined using qPCR. Intriguingly, when we treated KO BMDCs with the Sec22b-targeting shRNA, we again observed a reduction in cross-presentation (p <0.05). The reduction was comparable to that found in Sec22b-targeting shRNA-treated FL and WT BMDCs. Taken together, our data (a) demonstrate that Sec22b is not necessary for cross-presentation, (b) suggest the existence of a novel critical mediator of cross-presentation that is also targeted by the shRNA sequence used and (c) caution against extrapolating mechanisms or phenotypes based on KD studies alone. Cebrian, I. et al. Sec22b regulates phagosomal maturation and antigen crosspresentation by dendritic cells. Cell147, 1355-1368 (2011). Disclosures No relevant conflicts of interest to declare.

scholarly journals Subsets of mononuclear phagocytes are enriched in the inflamed colons of patients with IBD

2019 ◽  
Vol 20 (1) ◽  
Author(s):  
Hong Liu ◽  
Suryasarathi Dasgupta ◽  
Yu Fu ◽  
Brandi Bailey ◽  
Christian Roy ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Disease Severity ◽  
Immune Cells ◽  
Immune Cell ◽  
Treatment Resistance ◽  
In Silico Analysis ◽  
Cell Types ◽  
Mononuclear Phagocyte ◽  
Mononuclear Phagocytes

Abstract Background Myeloid cells, especially mononuclear phagocytes, which include monocytes, macrophages and dendritic cells (DC), play vital roles in innate immunity, and in the initiation and maintenance of adaptive immunity. While T cell-associated activation pathways and cytokines have been identified and evaluated in inflammatory bowel disease (IBD) patients (Neurath, Nat Rev Gastroenterol Hepatol 14:269–78, 1989), the role of mononuclear phagocytes are less understood. Recent reports support the crucial role of DC subsets in the development of acute colitis models (Arimura et al., Mucosal Immunol 10:957–70, 2017), and suggest they may contribute to the pathogenesis of ulcerative colitis (UC) by inducing Th1/Th2/Th17 responses (Matsuno et al., Inflamm Bowel Dis 23:1524–34, 2017). Results We performed in silico analysis and evaluated the enrichment of immune cells, with a focus on mononuclear phagocytes in IBD patient colonic biopsies. Samples were from different gut locations, with different levels of disease severity, and with treatment response to current therapies. We observe enrichment of monocytes, M1 macrophages, activated DCs (aDCs) and plasmacytoid dendritic cells (pDCs) in inflamed tissues from various gut locations. This enrichment correlates with disease severity. Additionally, the same mononuclear phagocytes subsets are among the top enriched cell types in both infliximab and vedolizumab treatment non-responder samples. We further investigated the enrichment of selected DC and monocyte subsets based on gene signatures derived from a DC- and monocyte-focused single cell RNA-seq (scRNA-seq) study (Villani et al., Science 356:eaah4573, 2017), and verified enrichment in both inflamed tissues and those with treatment resistance. Moreover, we validated an increased mononuclear phagocyte subset abundance in a Dextran Sulphate Sodium (DSS) induced colitis model in C57Bl/6 mice representative of chronic inflammation. Conclusions We conducted an extensive analysis of immune cell populations in IBD patient colonic samples and identified enriched subsets of monocytes, macrophages and dendritic cells in inflamed tissues. Understanding how they interact with other immune cells and other cells in the colonic microenvironment such as epithelial and stromal cells will help us to delineate disease pathogenesis.

scholarly journals Histamine Improves Antigen Uptake and Cross-Presentation by Dendritic Cells

2007 ◽  
Vol 179 (6) ◽  
pp. 3425-3433 ◽  
Author(s):  
Maria Marta Amaral ◽  
Carlos Davio ◽  
Ana Ceballos ◽  
Gabriela Salamone ◽  
Cristian Cañones ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Antigen Uptake ◽  
Cross Presentation

scholarly journals Incoming Human Cytomegalovirus pp65 (UL83) Contained in Apoptotic Infected Fibroblasts Is Cross-Presented to CD8+ T Cells by Dendritic Cells

2000 ◽  
Vol 74 (21) ◽  
pp. 10018-10024 ◽  
Author(s):  
Géraldine Arrode ◽  
Claire Boccaccio ◽  
Jacqueline Lulé ◽  
Sophie Allart ◽  
Nathalie Moinard ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Human Cytomegalovirus ◽  
Matrix Protein ◽  
Immune Escape ◽  
Apoptotic Cells ◽  
Necrosis Factor Alpha ◽  
Cross Presentation ◽  
The Matrix ◽  
Antigen Presenting

ABSTRACT Human cytomegalovirus (HCMV) infection is well controlled mainly by cytotoxic CD8+ T lymphocytes (CTL) directed against the matrix protein pp65 despite the numerous immune escape mechanisms developed by the virus. Dendritic cells (DCs) are key antigen-presenting cells for the generation of an immune response which have the capacity to acquire antigens via endocytosis of apoptotic cells and thus present peptides to major histocompatibility complex class I-restricted T cells. We examined whether this mechanism could contribute to the activation of anti-pp65 CTL. In this study, we show that infection by HCMV AD169 induced sensitization of MRC5 fibroblasts to tumor necrosis factor alpha-mediated apoptosis very early after virus inoculation and that pp65 contained in apoptotic cells came from the delivery of the matrix protein into the cell. We observed that immature DCs derived from peripheral monocytes were not permissive to HCMV AD169 infection but were able to internalize pp65-positive apoptotic infected MRC5 cells. We then demonstrated that following exposure to these apoptotic bodies, DCs could activate HLA-A2- or HLA-B35-restricted anti-pp65 CTL, suggesting that they acquired and processed properly fibroblast-derived pp65. Together, our data suggest that cross-presentation of incoming pp65 contained in apoptotic cells may provide a quick and efficient way to prime anti-HCMV CD8+ T cells.

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