scholarly journals Targeting human Plasmacytoid dendritic cells through BDCA2 prevents inflammation and fibrosis in xenotransplant mouse model of Scleroderma

2020 ◽  
Author(s):  
Rebecca L. Ross ◽  
Clarissa Corinaldesi ◽  
Gemma Migneco ◽  
Ian Carr ◽  
Agne Antanaviciute ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Skin Inflammation ◽  
Plasmacytoid Dendritic Cells ◽  
Preclinical Models ◽  
Fibrotic Response ◽  
Inhibitory Type ◽  
Immunocompromised Mice ◽  
Tlr Signalling

AbstractPlasmacytoid dendritic cells (pDC) have been implicated in the pathogenesis of Scleroderma (SSc) through their ability to infiltrate the skin and secrete interferons (IFN) and proinflammatory chemokines. Blood Dendritic Cells Antigen 2 (BDCA2) is an inhibitory type II C-type lectin expressed by human pDC. Here we determined the effects of BDCA2 internalisation on pDC mediated skin inflammation and fibrosis in human preclinical models of skin inflammation and fibrosis in vitro and in vivo. BDCA2 targeting reversed TLR-signalling induced transcriptome and differentiation of pDC and suppressed their ability to induce IFN response in organotypic 3D human skin cultures in vitro. In vivo, xenotransplantation of human pDC into immunocompromised mice (XenoSCID) significantly increased IFN induced responses to topical TLR7/9 agonist and separately enhanced the fibrotic response to bleomycin. Targeting of BDCA2 strongly suppressed both of these pathological responses ameliorating skin inflammation and fibrosis. Together, these preclinical data strongly support the notion that human pDC play a key role in immune driven skin fibrosis, which can be effectively blocked by targeting BDCA2.

scholarly journals TLR-activated plasmacytoid dendritic cells inhibit breast cancer cell growth in vitro and in vivo

Oncotarget ◽  
2016 ◽  
Vol 8 (7) ◽  
pp. 11708-11718 ◽  
Author(s):  
Jing Wu ◽  
Shuang Li ◽  
Yang Yang ◽  
Shan Zhu ◽  
Mingyou Zhang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Dendritic Cells ◽  
Cell Growth ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Plasmacytoid Dendritic Cells ◽  
Cancer Cell Growth ◽  
Breast Cancer Cell Growth

scholarly journals Plasmacytoid dendritic cells cross-prime naive CD8 T cells by transferring antigen to conventional dendritic cells through exosomes

2020 ◽  
Vol 117 (38) ◽  
pp. 23730-23741 ◽  
Author(s):  
Chunmei Fu ◽  
Peng Peng ◽  
Jakob Loschko ◽  
Li Feng ◽  
Phuong Pham ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Cd8 T Cells ◽  
Critical Role ◽  
Plasmacytoid Dendritic Cells ◽  
Viral Immunity ◽  
Cell Immunity ◽  
Antigen Transfer

Although plasmacytoid dendritic cells (pDCs) have been shown to play a critical role in generating viral immunity and promoting tolerance to suppress antitumor immunity, whether and how pDCs cross-prime CD8 T cells in vivo remain controversial. Using a pDC-targeted vaccine model to deliver antigens specifically to pDCs, we have demonstrated that pDC-targeted vaccination led to strong cross-priming and durable CD8 T cell immunity. Surprisingly, cross-presenting pDCs required conventional DCs (cDCs) to achieve cross-priming in vivo by transferring antigens to cDCs. Taking advantage of an in vitro system where only pDCs had access to antigens, we further demonstrated that cross-presenting pDCs were unable to efficiently prime CD8 T cells by themselves, but conferred antigen-naive cDCs the capability of cross-priming CD8 T cells by transferring antigens to cDCs. Although both cDC1s and cDC2s exhibited similar efficiency in acquiring antigens from pDCs, cDC1s but not cDC2s were required for cross-priming upon pDC-targeted vaccination, suggesting that cDC1s played a critical role in pDC-mediated cross-priming independent of their function in antigen presentation. Antigen transfer from pDCs to cDCs was mediated by previously unreported pDC-derived exosomes (pDCexos), that were also produced by pDCs under various conditions. Importantly, all these pDCexos primed naive antigen-specific CD8 T cells only in the presence of bystander cDCs, similarly to cross-presenting pDCs, thus identifying pDCexo-mediated antigen transfer to cDCs as a mechanism for pDCs to achieve cross-priming. In summary, our data suggest that pDCs employ a unique mechanism of pDCexo-mediated antigen transfer to cDCs for cross-priming.

scholarly journals Development of plasmacytoid dendritic cells in bone marrow stromal cell niches requires CXCL12-CXCR4 chemokine signaling

Blood ◽  
2007 ◽  
Vol 110 (13) ◽  
pp. 4153-4160 ◽  
Author(s):  
Hiroshi Kohara ◽  
Yoshiki Omatsu ◽  
Tatsuki Sugiyama ◽  
Mamiko Noda ◽  
Nobutaka Fujii ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Dendritic Cells ◽  
Stromal Cell ◽  
Hematopoietic Cells ◽  
Plasmacytoid Dendritic Cells ◽  
Type I ◽  
Hematopoietic Stem ◽  
Chemokine Signaling

Plasmacytoid dendritic cells (pDCs), also known as type I interferon (IFN)–producingcells, are thought to play central roles in antiviral immunity and the pathogenesis of some autoimmune diseases. pDCs are produced from hematopoietic stem cells in bone marrow. However, the environmental regulation of the development of pDCs is not fully understood. Here, we show that the numbers of pDCs and their earliest progenitors are severely reduced in the absence of CXCR4, the primary physiologic receptor for CXC chemokine ligand 12 (CXCL12), also known as stromal cell–derived factor-1 (SDF-1) in vivo. In vitro, CXCL12 induces a significant increase in pDC numbers generated from primitive hematopoietic cells, and pDCs and their progenitors migrate to CXCL12. In addition, most pDCs are in contact with CXCL12-abundant reticular (CAR) cells in the intersinal space of bone marrow, although many primitive hematopoietic cells adjoin CAR cells surrounding sinusoidal endothelial cells or residing near the bone surface. Thus we identified CXCL12 as a key regulator of pDC development produced by cellular niches, providing new targets for pDC therapeutic control.

scholarly journals Orthotopic Patient-Derived Xenografts of Gastric Cancer to Decipher Drugs Effects on Cancer Stem Cells and Metastatic Dissemination

Cancers ◽  
2019 ◽  
Vol 11 (4) ◽  
pp. 560 ◽  
Author(s):  
Julie Giraud ◽  
Damien Bouriez ◽  
Lornella Seeneevassen ◽  
Benoit Rousseau ◽  
Elodie Sifré ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Stem Cells ◽  
Cancer Stem Cells ◽  
Mouse Models ◽  
Distant Metastases ◽  
Preclinical Models ◽  
Immunocompromised Mice ◽  
Orthotopic Xenografts

Gastric cancer is the third leading cause of cancer mortality worldwide. Cancer stem cells (CSC) are at the origin of tumor initiation, chemoresistance, and the formation of metastases. However, there is a lack of mouse models enabling the study of the metastatic process in gastric adenocarcinoma (GC). The aims of this study were to develop original mouse models of patient-derived primary GC orthotopic xenografts (PDOX) allowing the development of distant metastases as preclinical models to study the anti-metastatic efficiency of drugs such as the phosphatidylinositol 3-kinase (PI3K) inhibitor Buparlisib (BKM120). Luciferase-encoding cells generated from primary GC were injected into the stomach wall of immunocompromised mice; gastric tumor and metastases development were followed by bioluminescence imaging. The anti-CSC properties of BKM120 were evaluated on the GC cells’ phenotype (CD44 expression) and tumorigenic properties in vitro and in vivo on BKM120-treated mice. After eight weeks, PDOX mice formed tumors in the stomach as well as distant metastases, that were enriched in CSC, in the liver, the lung, and the peritoneal cavity. BKM120 treatment significantly inhibited the CSC properties in vitro and reduced the number of distant metastases in mice. These new preclinical models offer the opportunity to study the anti-metastatic efficiency of new CSC-based therapeutic strategies.

scholarly journals Dengue Virus Activates Membrane TRAIL Relocalization and IFN-α Production by Human Plasmacytoid Dendritic Cells In Vitro and In Vivo

2013 ◽  
Vol 7 (6) ◽  
pp. e2257 ◽  
Author(s):  
Mariana Gandini ◽  
Christophe Gras ◽  
Elzinandes Leal Azeredo ◽  
Luzia Maria de Oliveira Pinto ◽  
Nikaïa Smith ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Dengue Virus ◽  
Plasmacytoid Dendritic Cells

scholarly journals CpG-matured Murine Plasmacytoid Dendritic Cells Are Capable of In Vivo Priming of Functional CD8 T Cell Responses to Endogenous but Not Exogenous Antigens

2004 ◽  
Vol 199 (4) ◽  
pp. 567-579 ◽  
Author(s):  
Mariolina Salio ◽  
Michael J. Palmowski ◽  
Ann Atzberger ◽  
Ian F. Hermans ◽  
Vincenzo Cerundolo
Keyword(s):  
Dendritic Cells ◽  
Plasmacytoid Dendritic Cells ◽  
Type I ◽  
Type I Ifn ◽  
Antiviral Responses ◽  
Specific Ctls ◽  
Antigen Presenting

Plasmacytoid dendritic cells (PDCs) are a unique leukocyte population capable of secreting high levels of type I interferon (IFN) in response to viruses and bacterial stimuli. In vitro experiments have shown that upon maturation, human and murine PDCs develop into potent immunostimulatory cells; however, their ability to prime an immune response in vivo remains to be addressed. We report that CpG-matured murine PDCs are capable of eliciting in naive mice antigen-specific CTLs against endogenous antigens as well as exogenous peptides, but not against an exogenous antigen. Type I IFN is not required for priming, as injection of CpG-matured PDCs into type I IFN receptor–deficient mice elicits functional CTL responses. Mature PDCs prime CTLs that secrete IFN-γ and protect mice from a tumor challenge. In contrast, immature PDCs are unable to prime antigen-specific CTLs. However, mice injected with immature PDCs are fully responsive to secondary antigenic challenges, suggesting that PDCs have not induced long-lasting tolerance via anergic or regulatory T cells. Our results underline the heterogeneity and plasticity of different antigen-presenting cells, and reveal an important role of mature PDCs in priming CD8 responses to endogenous antigens, in addition to their previously reported ability to modulate antiviral responses via type I IFN.

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