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Journal articles on the topic 'Clec9A'

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Published: 10 December 2022

Last updated: 29 January 2023

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1

Caminschi, Irina, Anna I. Proietto, Fatma Ahmet, Susie Kitsoulis, Joo Shin Teh, Jennifer C. Y. Lo, Alexandra Rizzitelli, et al. "The dendritic cell subtype-restricted C-type lectin Clec9A is a target for vaccine enhancement." Blood 112, no. 8 (October 15, 2008): 3264–73. http://dx.doi.org/10.1182/blood-2008-05-155176.

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Abstract A novel dendritic cell (DC)–restricted molecule, Clec9A, was identified by gene expression profiling of mouse DC subtypes. Based on sequence similarity, a human ortholog was identified. Clec9A encodes a type II membrane protein with a single extracellular C-type lectin domain. Both the mouse Clec9A and human CLEC9A were cloned and expressed, and monoclonal antibodies (mAbs) against each were generated. Surface staining revealed that Clec9A was selective for mouse DCs and was restricted to the CD8+ conventional DC and plasmacytoid DC subtypes. A subset of human blood DCs also expressed CLEC9A. A single injection of mice with a mAb against Clec9A, which targets antigens (Ags) to the DCs, produced a striking enhancement of antibody responses in the absence of added adjuvants or danger signals, even in mice lacking Toll-like receptor signaling pathways. Such targeting also enhanced CD4 and CD8 T-cell responses. Thus, Clec9A serves as a new marker to distinguish subtypes of both mouse and human DCs. Furthermore, targeting Ags to DCs with antibodies to Clec9A is a promising strategy to enhance the efficiency of vaccines, even in the absence of adjuvants.

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Schreibelt, Gerty, Lieke J. J. Klinkenberg, Luis J. Cruz, Paul J. Tacken, Jurjen Tel, Martin Kreutz, Gosse J. Adema, Gordon D. Brown, Carl G. Figdor, and I. Jolanda M. de Vries. "The C-type lectin receptor CLEC9A mediates antigen uptake and (cross-)presentation by human blood BDCA3+ myeloid dendritic cells." Blood 119, no. 10 (March 8, 2012): 2284–92. http://dx.doi.org/10.1182/blood-2011-08-373944.

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Abstract CLEC9A is a recently discovered C-type lectin receptor involved in sensing necrotic cells. In humans, this receptor is selectively expressed by BDCA3+ myeloid dendritic cells (mDCs), which have been proposed to be the main human cross-presenting mDCs and may represent the human homologue of murine CD8+ DCs. In mice, it was demonstrated that antigens delivered with antibodies to CLEC9A are presented by CD8+ DCs to both CD4+ and CD8+ T cells and induce antitumor immunity in a melanoma model. Here we assessed the ability of CLEC9A to mediate antigen presentation by human BDCA3+ mDCs, which represent < 0.05% of peripheral blood leukocytes. We demonstrate that CLEC9A is only expressed on immature BDCA3+ mDCs and that cell surface expression is lost after TLR-mediated maturation. CLEC9A triggering via antibody binding rapidly induces receptor internalization but does not affect TLR-induced cytokine production or expression of costimulatory molecules. More importantly, antigens delivered via CLEC9A antibodies to BDCA3+ mDCs are presented by both MHC class I (cross-presentation) and MHC class II to antigen-specific T cells. We conclude that CLEC9A is a promising target for in vivo antigen delivery in humans to increase the efficiency of vaccines against infectious or malignant diseases.

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Ito, Fumito, Mark D. Long, Ryutaro Kajihara, Satoko Matsueda, Takaaki Oba, Kazunori Kanehira, Song Liu, and Kenichi Makino. "Notch signaling is required for generation of conventional type 1 dendritic cells from human induced pluripotent stem cells." Journal of Immunology 208, no. 1_Supplement (May 1, 2022): 47.07. http://dx.doi.org/10.4049/jimmunol.208.supp.47.07.

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Abstract Compelling evidence shows a critical role of conventional type 1 dendritic cells (cDC1) in T-cell mediated antitumor immunity; however, obtaining large numbers of cDC1 is difficult. Theoretically, this limitation can be overcome by using induced pluripotent stem cells (iPSC) that could provide an unlimited source of autologous cDC1. However, generation of cDC1 from human iPSC remains elusive. Here, we hypothesized that Notch signaling would facilitate generation of cDC1 from human iPSC. We found that human iPSC gave rise to CD141+XCR1+CLEC9A+HLA-DR+ cells on OP9 feeder cells expressing the Notch ligand delta-like 1 (OP9-DL1) while the majority of iPSC-derived cells differentiated on OP9 cells were monocytic cells. Single-cell RNA sequencing analyses confirmed the presence of cDC1 as well as identified the heterogeneity of iPSC-derived CD1c+ cells; cDC2A, cDC2B, CD5+cDC2, and DC3. Inhibition of Notch signaling during co-culture of iPSC-derived CD34+ hematopoietic progenitor cells with OP9-DL1 cells abrogated generation of cDC1, and made expression of CD5, CLEC4A, CLEC10A and CD163 in CD1c+ DC similar to those differentiated on OP9 cells. Notch-activated human iPSC-derived XCR1+CLEC9A+HLA-DR+CD11c+ cells exhibited similar gene expression profile with peripheral blood cDC1, and phagocytotic, T-cell proliferative, and cytokine producing functions. Our study demonstrates that Notch signaling is required for the differentiation of cDC1-like cells, and facilitates generation of various cDC subsets from human iPSC. These findings provide insights into the future development of personalized treatment with unlimited numbers of autologous cDC1 from human iPSC. This work was supported by National Cancer Institute (NCI) grant P30CA016056 involving the use of Roswell Park’s Flow and Image Cytometry, Bioinformatics, and Genomic Shared Resources. This work was supported by the Melanoma Research Alliance and the Sarcoma Foundation of America (F. Ito), Uehara Memorial Foundation (T. Oba), and National Cancer Institute (NCI) grant, U24CA232979 (M. Long and S. Liu), K08CA197966 and R01CA255240-01A1 (F. Ito).

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4

Masterman, Kelly-Anne, Oscar L. Haigh, Kirsteen M. Tullett, Ingrid M. Leal-Rojas, Carina Walpole, Frances E. Pearson, Jonathon Cebon, et al. "Human CLEC9A antibodies deliver NY-ESO-1 antigen to CD141+ dendritic cells to activate naïve and memory NY-ESO-1-specific CD8+ T cells." Journal for ImmunoTherapy of Cancer 8, no. 2 (July 2020): e000691. http://dx.doi.org/10.1136/jitc-2020-000691.

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BackgroundDendritic cells (DCs) are crucial for the efficacy of cancer vaccines, but current vaccines do not harness the key cDC1 subtype required for effective CD8+ T-cell-mediated tumor immune responses. Vaccine immunogenicity could be enhanced by specific delivery of immunogenic tumor antigens to CD141+ DCs, the human cDC1 equivalent. CD141+ DCs exclusively express the C-type-lectin-like receptor CLEC9A, which is important for the regulation of CD8+ T cell responses. This study developed a new vaccine that harnesses a human anti-CLEC9A antibody to specifically deliver the immunogenic tumor antigen, NY-ESO-1 (New York esophageal squamous cell carcinoma 1), to human CD141+ DCs. The ability of the CLEC9A-NY-ESO-1 antibody to activate NY-ESO-1-specific naïve and memory CD8+ T cells was examined and compared with a vaccine comprised of a human DEC-205-NY-ESO-1 antibody that targets all human DCs.MethodsHuman anti-CLEC9A, anti-DEC-205 and isotype control IgG4 antibodies were genetically fused to NY-ESO-1 polypeptide. Cross-presentation to NY-ESO-1-epitope-specific CD8+ T cells and reactivity of T cell responses in patients with melanoma were assessed by interferon γ (IFNγ) production following incubation of CD141+ DCs and patient peripheral blood mononuclear cells with targeting antibodies. Humanized mice containing human DC subsets and a repertoire of naïve NY-ESO-1-specific CD8+ T cells were used to investigate naïve T cell priming. T cell effector function was measured by expression of IFNγ, MIP-1β, tumor necrosis factor and CD107a and by lysis of target tumor cells.ResultsCLEC9A-NY-ESO-1 antibodies (Abs) were effective at mediating delivery and cross-presentation of multiple NY-ESO-1 epitopes by CD141+ DCs for activation of NY-ESO-1-specific CD8+ T cells. When benchmarked to NY-ESO-1 conjugated to an untargeted control antibody or to anti-human DEC-205, CLEC9A-NY-ESO-1 was superior at ex vivo reactivation of NY-ESO-1-specific T cell responses in patients with melanoma. Moreover, CLEC9A-NY-ESO-1 induced priming of naïve NY-ESO-1-specific CD8+ T cells with polyclonal effector function and potent tumor killing capacity in vitro.ConclusionsThese data advocate human CLEC9A-NY-ESO-1 Ab as an attractive strategy for specific targeting of CD141+ DCs to enhance tumor immunogenicity in NY-ESO-1-expressing malignancies.

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5

Bell, Elaine. "CLEC9A: linking necrosis and immunity." Nature Reviews Immunology 9, no. 4 (April 2009): 223. http://dx.doi.org/10.1038/nri2531.

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Masterman, Kelly-Anne, Oscar Haigh, Kirsteen Tullett, Ingrid Leal-Rojas, Carina Walpole, Frances Pearson, Jonathon Cebon, et al. "612 Human CLEC9A antibodies deliver NY-ESO-1 antigen to CD141+ dendritic cells to activate naïve and memory NY-ESO-1-specific CD8+ T cells." Journal for ImmunoTherapy of Cancer 8, Suppl 3 (November 2020): A648. http://dx.doi.org/10.1136/jitc-2020-sitc2020.0612.

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BackgroundDendritic cells (DC) are crucial for the efficacy of cancer vaccines, but current vaccines do not harness the key cDC1 subtype required for effective CD8+ T cell mediated tumor immune responses. Vaccine immunogenicity could be enhanced by specific delivery of immunogenic tumor antigens to CD141+ DC, the human cDC1 equivalent. CD141+ DC exclusively express the C-type-lectin-like receptor CLEC9A, which is important for the regulation of CD8+ T cell responses. This study developed a new vaccine that harnesses a human anti-CLEC9A antibody to specifically deliver the immunogenic tumor antigen, NY-ESO-1 to human CD141+ DC. The ability of the CLEC9A-NY-ESO-1 antibody to activate NY-ESO-1 specific naïve and memory CD8+ T cells was examined and compared to a vaccine comprised of a human DEC-205-NY-ESO-1 antibody that targets all human DC.MethodsHuman anti-CLEC9A, anti-DEC-205 and isotype control IgG4 antibodies were genetically fused to NY-ESO-1 polypeptide. Cross-presentation to NY-ESO-1- epitope specific CD8+ T cells and reactivity of T cell responses in melanoma patients was assessed by IFNγ production following incubation of CD141+ DC and patient peripheral blood mononuclear cells with targeting antibodies. Humanized mice containing human DC subsets and a repertoire of naïve NY-ESO-1-specific CD8+ T cells were used to investigate naïve T cell priming. T cell effector function was measured by expression of IFNγ, MIP-1β, TNF and CD107a and by lysis of target tumor cells.ResultsCLEC9A-NY-ESO-1 Ab were effective at mediating delivery and cross-presentation of multiple NY-ESO-1 epitopes by CD141+ DC for activation of NY-ESO-1-specific CD8+ T cells. When benchmarked to NY-ESO-1 conjugated to an untargeted control antibody or to anti-human DEC-205, CLEC9A-NY-ESO-1 was superior at ex vivo reactivation of NY-ESO-1-specific T cell responses in melanoma patients. Moreover, CLEC9A-NY-ESO-1 induced priming of naïve NY-ESO-1-specific CD8+ T cells with polyclonal effector function and potent tumor killing capacity in vitro.ConclusionsThese data advocate human CLEC9A-NY-ESO-1 antibody as an attractive strategy for specific targeting of CD141+ DC to enhance tumour immunogenicity in NY-ESO-1-expressing malignancies.Ethics ApprovalWritten informed consent was obtained for human sample acquisition in line with standards established by the Declaration of Helsinki. Study approval was granted by the Mater Human Research Ethics Committee (HREC13/MHS/83 and HREC13/MHS/86) and The U.S. Army Medical Research and Materiel Command (USAMRMC) Office of Research Protections, Human Research Protection Office (HRPO; A-18738.1, A-18738.2, A-18738.3). All animal experiments were approved by the University of Queensland Animal Ethics Committee and conducted in accordance with the Australian Code for the Care and Use of Animals for Scientific Purposes in addition to the laws of the United States and regulations of the Department of Agriculture.

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7

Haddad, Y., L. Laurans, S. Metghalchi, Z. Zeboudj, A. Giraud, Z. Mallat, and S. Taleb. "The role of CLEC9a in atherosclerosis development." Archives of Cardiovascular Diseases Supplements 9, no. 2 (April 2017): 184. http://dx.doi.org/10.1016/s1878-6480(17)30455-x.

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8

van der Aa, Evelyn, Nadine van Montfoort, and Andrea M. Woltman. "BDCA3+CLEC9A+ human dendritic cell function and development." Seminars in Cell & Developmental Biology 41 (May 2015): 39–48. http://dx.doi.org/10.1016/j.semcdb.2014.05.016.

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9

Park, Hae-Young, Amanda Light, Mireille H. Lahoud, Irina Caminschi, David M. Tarlinton, and Ken Shortman. "Evolution of B Cell Responses to Clec9A-Targeted Antigen." Journal of Immunology 191, no. 10 (October 11, 2013): 4919–25. http://dx.doi.org/10.4049/jimmunol.1301947.

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10

Shen, Lianjun, Janice BelleIsle, and Kenneth Rock. "Regulation of cross priming and anti-tumor immunity in vivo (107.2)." Journal of Immunology 188, no. 1_Supplement (May 1, 2012): 107.2. http://dx.doi.org/10.4049/jimmunol.188.supp.107.2.

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Abstract Cross priming plays an important role in immune surveillance against invading pathogens and cancers. The underlying mechanisms and regulation of this process, especially in vivo, are still not fully understood. The cross priming process in vivo is regulated and influenced by a number of factors at several levels. One factor is the state of the antigen donor cells. Another component is the contribution of innate immune receptors (TLR, CLR and NLR). We find that although the innate adaptor MyD88 is dispensable for cross priming of primary CD8 T cell responses, it is essential to generate long lasting anti-tumor immunity. Yet another factor that has been suggested is the participation of CD8α+Clec9a+ dendritic cells in cross presentation. However, we find that the primary CTL response primed by cell-associated antigen is largely unaffected or marginally compromised in mice lacking the CD8α+Clec9a+ DC subset, suggesting that other types of APCs also make a significant contribution. Taken together, many factors are involved in cross priming and its outcome.

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Macri, Christophe, Claire Dumont, Scott Panozza, Mireille H. Lahoud, Irina Caminschi, Jose A. Villadangos, Angus P. R. Johnston, and Justine D. Mintern. "Antibody-mediated targeting of antigen to C-type lectin-like receptors Clec9A and Clec12A elicits different vaccination outcomes." Molecular Immunology 81 (January 2017): 143–50. http://dx.doi.org/10.1016/j.molimm.2016.12.010.

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12

Kauke, Monique, Nikki Ross, Dalia Burzyn, Shelly Martin, Ke Xu, Nuruddeen Lewis, Charan Leng, et al. "703 Engineered exosomes with altered cellular tropism achieve targeted STING agonist delivery and single-agent tumor control in vivo." Journal for ImmunoTherapy of Cancer 8, Suppl 3 (November 2020): A745. http://dx.doi.org/10.1136/jitc-2020-sitc2020.0703.

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BackgroundExosomes are natural, abundant extracellular vesicles capable of transferring complex molecules between neighboring and distant cell types. Translational research efforts have focused on co-opting this communication mechanism to deliver exogenous payloads to treat a variety of diseases. Important strategies to maximize the therapeutic potential of exosomes therefore include payload loading, functionalization of the exosome surface with pharmacologically active proteins, and delivery to target cells of interest.MethodsThrough comparative proteomic analysis of purified exosomes, we identified several highly enriched and exosome-specific proteins, including a transmembrane glycoprotein (PTGFRN) belonging to the immunoglobulin superfamily. Leveraging PTGFRN as a scaffold for exosome surface display, we developed our engExTM platform to generate engineered exosomes functionalized with a variety of structurally and biologically diverse proteins.Systemically administered exosomes are primarily taken up by macrophages in the liver and spleen. To redirect exosome uptake to other cell types, we employed our engineering platform to display functional targeting ligands, including single domain antibodies, single chain variable fragments, single chain Fabs (scFabs), and receptor ligands, on the exosome surface at high density. To demonstrate that exosome surface modifications can alter cellular tropism, we generated exosomes displaying anti-Clec9A scFabs to target conventional type 1 dendritic cells (cDC1s), anti-CD3 scFabs to target T cells, and CD40 ligand to target B cells. The engineered exosomes exhibited functional antigen binding that led to greater association with the cell types expressing the cognate receptor both in vitro and in vivo.ResultsIn mice, systemic administration of exosomes engineered to display scFabs targeting Clec9A resulted in a 4-fold increase in the percentage of cDC1 cells in the blood that had taken up exosomes over controls, and a 6-fold increase in the number of exosomes taken up per cell. We further showed that compared to untargeted exosomes, those with altered tropism achieved increased functional payload delivery to the target cell of interest. In primary mouse dendritic cells, anti-Clec9A exosomes loaded with a cyclic dinucleotide STING agonist achieved greater pathway induction, 2.3-fold greater as measured by IFNβ production, 2-fold by IFNα, and 15-fold by IL-12, when compared to an untargeted control. Preliminary in vivo data show that intra-tumorally administered anti-Clec9A exosomes reduce the required STING agonist dose 10-fold to achieve single-agent tumor control and induce immune responses against tumor-associated antigen, compared to controls.ConclusionsThese results demonstrate the potential of our engExTM platform to generate targeted exosome therapeutics capable of immune cell stimulation and tumor growth inhibition in vivo.Ethics ApprovalAll experimental animal studies were performed according to Codiak BioSciences IACUC approved AUP CB2020-001.

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Steinle, Alexander, Veronika Stejfova, Sabrina Kuttruff, Birgit Schittek, and Jessica Spreu. "CLEC2A Is a Novel Skin-Specific, Stimulatory Ligand of Human NK Cells (39.8)." Journal of Immunology 182, no. 1_Supplement (April 1, 2009): 39.8. http://dx.doi.org/10.4049/jimmunol.182.supp.39.8.

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Abstract The Natural Killer Gene Complex (NKC) encodes for numerous C-type lectin-like receptors (CTLR) variably expressed on lymphocytes and myeloid cells. Well-known representatives of NKC-encoded CTLR are NKG2D, CD69, and Ly49 molecules. However, the NKC also contains a considerable number of genes which are barely characterized. Recently, we described the CLEC2A gene encoding for a new member of the human CLEC2 family of NKC-encoded CTLR. CLEC2A, in contrast to other human CLEC2 family members such as CD69/CLEC2C and AICL/CLEC2B, is virtually not expressed by peripheral leukocytes, but its expression appears restricted to skin. We now report that CLEC2A encodes for a non-disulfide-linked, homodimeric surface CTLR which is expressed on freshly isolated skin cells. Addressing a potential immune-associated function, we find that CLEC2A stimulates cytotoxicity and cytokine release of human NK cells. However, we failed to ascertain CLEC2A engagement by known activating NK receptors. Instead, we identified a hitherto undescribed NKC-encoded CTLR (NKp65) that specifically interacts with CLEC2A and activates NK cytotoxicity. In summary, we define CLEC2A as a skin-specific and NK cell-stimulating CTLR engaging NKp65, a novel activating CTLR which may allow for dedicated immunosurveillance of human skin. This work was supported by funds (SFB 685/A1) of the German Research Foundation (DFG).

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Chen, Yu-Pei, Jian-Hua Yin, Wen-Fei Li, Han-Jie Li, Dong-Ping Chen, Cui-Juan Zhang, Jia-Wei Lv, et al. "Single-cell transcriptomics reveals regulators underlying immune cell diversity and immune subtypes associated with prognosis in nasopharyngeal carcinoma." Cell Research 30, no. 11 (July 20, 2020): 1024–42. http://dx.doi.org/10.1038/s41422-020-0374-x.

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Abstract Nasopharyngeal carcinoma (NPC) is an aggressive malignancy with extremely skewed ethnic and geographic distributions. Increasing evidence indicates that targeting the tumor microenvironment (TME) represents a promising therapeutic approach in NPC, highlighting an urgent need to deepen the understanding of the complex NPC TME. Here, we generated single-cell transcriptome profiles for 7581 malignant cells and 40,285 immune cells from fifteen primary NPC tumors and one normal sample. We revealed malignant signatures capturing intratumoral transcriptional heterogeneity and predicting aggressiveness of malignant cells. Diverse immune cell subtypes were identified, including novel subtypes such as CLEC9A+ dendritic cells (DCs). We further revealed transcriptional regulators underlying immune cell diversity, and cell–cell interaction analyses highlighted promising immunotherapeutic targets in NPC. Moreover, we established the immune subtype-specific signatures, and demonstrated that the signatures of macrophages, plasmacytoid dendritic cells (pDCs), CLEC9A+ DCs, natural killer (NK) cells, and plasma cells were significantly associated with improved survival outcomes in NPC. Taken together, our findings represent a unique resource providing in-depth insights into the cellular heterogeneity of NPC TME and highlight potential biomarkers for anticancer treatment and risk stratification, laying a new foundation for precision therapies in NPC.

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Tullett, Kirsteen M., Peck Szee Tan, Hae-Young Park, Ralf B. Schittenhelm, Nicole Michael, Marnie Blewitt, Irina Caminschi, et al. "The dendritic cell receptor Clec9A: receptor regulation and immune modulation." Molecular Immunology 150 (October 2022): 15–16. http://dx.doi.org/10.1016/j.molimm.2022.05.058.

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Masterman, K. A., F. E. Pearson, K. Tullett, O. Haigh, C. Walpole, G. Daraj, M. H. Lahoud, I. Leal Rojas, and K. Radford. "Targeting human CD141+ DC using CLEC9A antibodies for cancer immunotherapy." Annals of Oncology 29 (December 2018): x35—x36. http://dx.doi.org/10.1093/annonc/mdy487.033.

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Goodfield, Laura L., Johanna Lahdenranta, Heather Scott, Tamera Ashworth, Lia Luus, Anna F. Licht, Kevin McDonnell, Phil Brandish, and Nicholas Keen. "Abstract 4230: Modeling the cDC1 ex vivo and in vitro: Development and comparison of a conventional dendritic cell culture system for industry." Cancer Research 82, no. 12_Supplement (June 15, 2022): 4230. http://dx.doi.org/10.1158/1538-7445.am2022-4230.

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Abstract Conventional dendritic cells (cDC) are innate immune cells specialized in antigen sampling and subsequent cross-presentation to immune cells and are critical for an effective anti-tumor immune response. While crucial to immunity against intracellular pathogens, viruses, and tumors, cDC type I (cDC1) are a relatively rare population and constitute about 0.05% of cells in the blood. Using these rare cells in screening assays can be a challenge, as very small proportions are found in peripheral human blood and since they are difficult to isolate with high viability and purity. Existing methods to generate acceptable numbers of cDC1s require a feeder cell line, which is not accessible to many laboratories. Using a systematic approach, we developed a scalable differentiation system to generate a mixed culture containing cDC1 cells from CD34+ hematopoietic stem cells isolated from cord blood that does not require feeder cells. This culture of cells has been phenotypically and functionally characterized to express high levels of CD141 and Clec9a, as well as responsiveness to various activating stimuli including poly (I:C). Cells derived from this culture method express similar levels of CD141 and Clec9a compared to those observed in peripheral blood of healthy donors. Our effort to find a less laborious, more efficient system includes comparison to cDC1 responses from an in vitro differentiation system to cDC1s isolated from humanized mouse bone marrow, with evaluation of both surface marker phenotype and responsiveness to activating stimuli. We also compared the responses of these cells to monocyte derived dendritic cells that express CD141 and Clec9a. These data demonstrate that the HSC-derived cDC1 cultures provide a comparison of unique dendritic cells that may be utilized for screening assays in an industry setting. Citation Format: Laura L. Goodfield, Johanna Lahdenranta, Heather Scott, Tamera Ashworth, Lia Luus, Anna F. Licht, Kevin McDonnell, Phil Brandish, Nicholas Keen. Modeling the cDC1 ex vivo and in vitro: Development and comparison of a conventional dendritic cell culture system for industry [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4230.

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Yan, Zhongyi, Yahong Wu, Jiangfeng Du, Guodong Li, Shengdian Wang, Wenpeng Cao, Xiuman Zhou, et al. "A novel peptide targeting Clec9a on dendritic cell for cancer immunotherapy." Oncotarget 7, no. 26 (May 26, 2016): 40437–50. http://dx.doi.org/10.18632/oncotarget.9624.

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Piva, Lucia, Piotr Tetlak, Carla Claser, Klaus Karjalainen, Laurent Renia, and Christiane Ruedl. "Cutting Edge: Clec9A+ Dendritic Cells Mediate the Development of Experimental Cerebral Malaria." Journal of Immunology 189, no. 3 (June 25, 2012): 1128–32. http://dx.doi.org/10.4049/jimmunol.1201171.

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20

Xu, Feifei, Zining Wang, Hongxia Zhang, Jiemin Chen, Xiaojuan Wang, Lei Cui, Chunyuan Xie, et al. "Mevalonate Blockade in Cancer Cells Triggers CLEC9A+ Dendritic Cell-Mediated Antitumor Immunity." Cancer Research 81, no. 17 (July 15, 2021): 4514–28. http://dx.doi.org/10.1158/0008-5472.can-20-3977.

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Zeng, Bijun, Anton P. J. Middelberg, Adrian Gemiarto, Kelli MacDonald, Alan G. Baxter, Meghna Talekar, Davide Moi, et al. "Self-adjuvanting nanoemulsion targeting dendritic cell receptor Clec9A enables antigen-specific immunotherapy." Journal of Clinical Investigation 128, no. 5 (April 9, 2018): 1971–84. http://dx.doi.org/10.1172/jci96791.

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22

Zhang, Jian-Guo, Peter E. Czabotar, Antonia N. Policheni, Irina Caminschi, Soo San Wan, Susie Kitsoulis, Kirsteen M. Tullett, et al. "The Dendritic Cell Receptor Clec9A Binds Damaged Cells via Exposed Actin Filaments." Immunity 36, no. 4 (April 2012): 646–57. http://dx.doi.org/10.1016/j.immuni.2012.03.009.

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Salei, Natallia, Stephan Rambichler, Johanna Salvermoser, Nikos E. Papaioannou, Ronja Schuchert, Dalia Pakalniškytė, Na Li, et al. "The Kidney Contains Ontogenetically Distinct Dendritic Cell and Macrophage Subtypes throughout Development That Differ in Their Inflammatory Properties." Journal of the American Society of Nephrology 31, no. 2 (January 13, 2020): 257–78. http://dx.doi.org/10.1681/asn.2019040419.

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BackgroundMononuclear phagocytes (MPs), including macrophages, monocytes, and dendritic cells (DCs), are phagocytic cells with important roles in immunity. The developmental origin of kidney DCs has been highly debated because of the large phenotypic overlap between macrophages and DCs in this tissue.MethodsWe used fate mapping, RNA sequencing, flow cytometry, confocal microscopy, and histo-cytometry to assess the origin and phenotypic and functional properties of renal DCs in healthy kidney and of DCs after cisplatin and ischemia reperfusion–induced kidney injury.ResultsAdult kidney contains at least four subsets of MPs with prominent Clec9a-expression history indicating a DC origin. We demonstrate that these populations are phenotypically, functionally, and transcriptionally distinct from each other. We also show these kidney MPs exhibit unique age-dependent developmental heterogeneity. Kidneys from newborn mice contain a prominent population of embryonic-derived MHCIInegF4/80hiCD11blow macrophages that express T cell Ig and mucin domain containing 4 (TIM-4) and MER receptor tyrosine kinase (MERTK). These macrophages are replaced within a few weeks after birth by phenotypically similar cells that express MHCII but lack TIM-4 and MERTK. MHCII+F4/80hi cells exhibit prominent Clec9a-expression history in adulthood but not early life, indicating additional age-dependent developmental heterogeneity. In AKI, MHCIInegF4/80hi cells reappear in adult kidneys as a result of MHCII downregulation by resident MHCII+F4/80hi cells, possibly in response to prostaglandin E2 (PGE2). RNA sequencing further suggests MHCII+F4/80hi cells help coordinate the recruitment of inflammatory cells during renal injury.ConclusionsDistinct developmental programs contribute to renal DC and macrophage populations throughout life, which could have important implications for therapies targeting these cells.

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Kassianos, Andrew J., Xiangju Wang, Sandeep Sampangi, Kimberly Muczynski, Helen Healy, and Ray Wilkinson. "Increased tubulointerstitial recruitment of human CD141hi CLEC9A+ and CD1c+ myeloid dendritic cell subsets in renal fibrosis and chronic kidney disease." American Journal of Physiology-Renal Physiology 305, no. 10 (November 15, 2013): F1391—F1401. http://dx.doi.org/10.1152/ajprenal.00318.2013.

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Dendritic cells (DCs) play critical roles in immune-mediated kidney diseases. Little is known, however, about DC subsets in human chronic kidney disease, with previous studies restricted to a limited set of pathologies and to using immunohistochemical methods. In this study, we developed novel protocols for extracting renal DC subsets from diseased human kidneys and identified, enumerated, and phenotyped them by multicolor flow cytometry. We detected significantly greater numbers of total DCs as well as CD141hi and CD1c+ myeloid DC (mDCs) subsets in diseased biopsies with interstitial fibrosis than diseased biopsies without fibrosis or healthy kidney tissue. In contrast, plasmacytoid DC numbers were significantly higher in the fibrotic group compared with healthy tissue only. Numbers of all DC subsets correlated with loss of kidney function, recorded as estimated glomerular filtration rate. CD141hi DCs expressed C-type lectin domain family 9 member A (CLEC9A), whereas the majority of CD1c+ DCs lacked the expression of CD1a and DC-specific ICAM-3-grabbing nonintegrin (DC-SIGN), suggesting these mDC subsets may be circulating CD141hi and CD1c+ blood DCs infiltrating kidney tissue. Our analysis revealed CLEC9A+ and CD1c+ cells were restricted to the tubulointerstitium. Notably, DC expression of the costimulatory and maturation molecule CD86 was significantly increased in both diseased cohorts compared with healthy tissue. Transforming growth factor-β levels in dissociated tissue supernatants were significantly elevated in diseased biopsies with fibrosis compared with nonfibrotic biopsies, with mDCs identified as a major source of this profibrotic cytokine. Collectively, our data indicate that activated mDC subsets, likely recruited into the tubulointerstitium, are positioned to play a role in the development of fibrosis and, thus, progression to chronic kidney disease.

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Ramos, Maria I., Marcel B. M. Teunissen, Boy Helder, Saida Aarrass, Maria J. H. de Hair, Arno W. van Kuijk, Danielle M. Gerlag, Paul P. Tak, and Maria C. Lebre. "Reduced CLEC9A expression in synovial tissue of psoriatic arthritis patients after adalimumab therapy." Rheumatology 55, no. 9 (May 13, 2016): 1575–84. http://dx.doi.org/10.1093/rheumatology/kew204.

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Caminschi, Irina, David Vremec, Fatma Ahmet, Mireille H. Lahoud, Jose A. Villadangos, Kenneth M. Murphy, William R. Heath, and Ken Shortman. "Antibody responses initiated by Clec9A-bearing dendritic cells in normal and Batf3−/− mice." Molecular Immunology 50, no. 1-2 (February 2012): 9–17. http://dx.doi.org/10.1016/j.molimm.2011.11.008.

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Lam, Pui Yeng, Takumi Kobayashi, Megan Soon, Bijun Zeng, Riccardo Dolcetti, Graham Leggatt, Ranjeny Thomas, and Stephen R. Mattarollo. "NKT Cell–Driven Enhancement of Antitumor Immunity Induced by Clec9a-Targeted Tailorable Nanoemulsion." Cancer Immunology Research 7, no. 6 (May 3, 2019): 952–62. http://dx.doi.org/10.1158/2326-6066.cir-18-0650.

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Fino, Kristin K., Linlin Yang, Sanmei Hu, Scott E. Halstead, Susan L. DiAngelo, Patricia Silveyra, and Zissis C. Chroneos. "SP-R210 (Myo18A) enhances influenza A virus pathogenicity by alveolar macrophages and dendritic cells in vivo." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 78.4. http://dx.doi.org/10.4049/jimmunol.196.supp.78.4.

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Abstract Alveolar macrophages (AMs) are critical for the host response to severe influenza A virus (IAV) infection; IAV is known to cause abortive infection in AMs that is thought to initiate the lung’s immune response to the virus. Our recent studies indicate that the surfactant protein A receptor SP-R210 mediates IAV entry in AMs. Based on these findings, we asked whether SP-R210 modulates the host response to IAV infection. To address this question, we used SP-R210 floxed mice to delete SP-R210 in CD11c-Cre (dendritic cells and AMs) or Clec9A-Cre (CD103+ dendritic cells) expressing cells. Mice were infected intranasally with a sublethal dose of 1,000 FFU IAV PR8 strain and morbidity was monitored daily by body weight. We found that disruption of SP-R210 significantly reduced susceptibility to infection in both CD11c-CRE/SPR210+/− and Clec9A-Cre/SP-R210+/− as indicated by accelerated body weight recovery 10 days after infection compared to control littermates. The increased recovery of SP-R210-deficient mice was accompanied by a faster decrease in viral titer 7 to 14 days post infection (dpi) as well as increased numbers of CD4+ and CD8+ T cells 14 dpi. Furthermore, flow cytometry analysis revealed significantly increased number of CD11b+Ly6C++Ly6G- and CD11b+SiglecF+ macrophages and AMs in SP-R210-deficient mice, respectively. Consistent with these results, real time qPCR showed persistent suppression of the AM marker SiglecF in control littermates whereas inhibition of SiglecF expression in SP-R210-deficient mice was transient returning to near normal levels by 14 dpi. Taken together, these findings support the model that IAV causes depletion of AMs through SP-R210 disrupting restoration of immune homeostasis after IAV infection.

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Hsieh, Shie-Liang. "CLEC18 family are novel C-type lectins with differential binding specificity to glycans and TLR ligands." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 203.4. http://dx.doi.org/10.4049/jimmunol.196.supp.203.4.

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Abstract The human C-type lectin 18 (clec18) gene cluster, which contains clec18a, clec18b and clec18c three loci, is located in human chromosome 16q22. Even though the amino acid sequences of CLEC18A, CLEC18B, and CLEC18C are almost identical, several amino acid residues located in the C-type lectin-like domain (CTLD) and the Sperm-Coating Protein/Tpx-1/Ag5/PR-1/Sc7 (SCP/TAPS) domain, also known as the cysteine-rich secretory proteins/antigen 5/pathogenesis-related 1 proteins (CAP) domain, are distinct from each other. Genotyping by real-time PCR and sequencing further shows the presence of multiple alleles in clec18a/b/c loci. Flow cytometry analysis demonstrates that CLEC18 (CLEC18A, B and C) are expressed abundantly in human peripheral blood cells. Moreover, CLEC18 expression is further upregulated when monocytes differentiate into macrophages and dendritic cells (DCs). Immunofluorescence staining reveals that CLEC18 are localized in the endoplasmic reticulum (ER), Golgi apparatus, and endosome. Interestingly, CLEC18 are also detectable in human sera and culture supernatants from primary cells and 293T cells overexpressing CLEC18. Moreover, CLEC18 bind polysaccharide in Ca2+–independent manner, and the amino acid residues S/R339 and D/N421 in CTLD domain contribute to their differential binding abilities to polysaccharides isolated from Ganoderma lucidum (GLPS-F3). The S339 (CLEC18A) and R339 (CLEC18A-1) displayed differential binding affinity to TLR ligands. Their roles to determine host responses to virus infection are under intensive investigation now.

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Kato, Yu, Ali Zaid, Gayle M. Davey, Scott N. Mueller, Stephen L. Nutt, Dimitra Zotos, David M. Tarlinton, et al. "Targeting Antigen to Clec9A Primes Follicular Th Cell Memory Responses Capable of Robust Recall." Journal of Immunology 195, no. 3 (June 22, 2015): 1006–14. http://dx.doi.org/10.4049/jimmunol.1500767.

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Cheng, An-Chieh, Kuang-Yao Yang, Nien-Jung Chen, Tsui-Ling Hsu, Ruwen Jou, Shie-Liang Hsieh, and Ping-Hui Tseng. "CLEC9A modulates macrophage-mediated neutrophil recruitment in response to heat-killed Mycobacterium tuberculosis H37Ra." PLOS ONE 12, no. 10 (October 24, 2017): e0186780. http://dx.doi.org/10.1371/journal.pone.0186780.

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Picco, Gianfranco, Richard Beatson, Joyce Taylor‐Papadimitriou, and Joy M. Burchell. "Targeting DNGR‐1 (CLEC9A) with antibody/MUC1 peptide conjugates as a vaccine for carcinomas." European Journal of Immunology 44, no. 7 (April 17, 2014): 1947–55. http://dx.doi.org/10.1002/eji.201344076.

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Li, Jessica, Fatma Ahmet, Lucy C. Sullivan, Andrew G. Brooks, Stephen J. Kent, Robert De Rose, Andres M. Salazar, et al. "Antibodies targeting Clec9A promote strong humoral immunity without adjuvant in mice and non-human primates." European Journal of Immunology 45, no. 3 (January 14, 2015): 854–64. http://dx.doi.org/10.1002/eji.201445127.

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Makino, Kenichi, Mark D. Long, Ryutaro Kajihara, Satoko Matsueda, Takaaki Oba, Kazunori Kanehira, Song Liu, and Fumito Ito. "Generation of cDC-like cells from human induced pluripotent stem cells via Notch signaling." Journal for ImmunoTherapy of Cancer 10, no. 1 (January 2022): e003827. http://dx.doi.org/10.1136/jitc-2021-003827.

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BackgroundDendritic cells (DCs) play critical roles in regulating the innate and adaptive immune responses, and have long been a major focus of cancer immunotherapy. Accumulating evidence suggests that conventional type 1 DCs (cDC1s) excel in cross-presentation of exogenous antigens on MHC-I molecules and induction of antitumor CD8+ T cell immunity; however, obtaining large numbers of cDC1s is difficult. The use of reprogramming and differentiation technology is advantageous for obtaining unlimited numbers of autologous cDC1s especially for therapeutic interventions where repeated vaccinations are required. However, generation of cDC1s from human induced pluripotent stem cells (iPSCs) remains elusive.MethodsHuman iPSCs established from peripheral blood T cells and monocytes were differentiated to myeloid cells under on-feeder or feeder-free culture conditions in vitro. Phenotype, genomic and transcriptomic signature, and function of human iPSC-derived DCs were analyzed. The role of Notch signaling for the generation of HLA-DR+ cells from human iPSCs was interrogated by a loss- and gain-of-function approach.ResultsFlow cytometric analyses and single-cell profiling of HLA-DR+ cells revealed that human iPSCs gave rise to CD141+XCR1+CLEC9A+ cells (cDC1s), CLEC4AhiCLEC10A–CD1c+ cells (cDC2As), CLEC4AloCLEC10A+CD1c+ cells (cDC2Bs), CD163–CD5+CD1c+ cells (CD5+cDC2s), and AXL+SIGLEC6+ cells (AS-DCs) on OP9 feeder cells expressing the Notch ligand delta-like 1 (OP9-DL1) while the majority of iPSC-derived cells differentiated on OP9 cells were CD163+CD5–CD1c+ cells (DC3s) and monocytes. Plasmacytoid DCs were not differentiated from iPSCs on either OP9 or OP9-DL1 cells. Inhibition of Notch signaling during co-culture of iPSC-derived CD34+ hematopoietic progenitor cells with OP9-DL1 cells abrogated generation of cDC1s, cDC2As, cDC2Bs, CD5+cDC2s, and AS-DCs but increased frequency of DC3s. Notch-activated human iPSC-derived XCR1+CLEC9A+HLA-DR+CD11c+ cells exhibited similar gene expression profile with peripheral blood cDC1s. Human iPSC-derived DCs have phagocytic, T-cell proliferative, and cytokine-producing functions.ConclusionsOur study demonstrates a critical role of Notch signaling in regulating developmental pathway of human cDCs. These findings provide insights into the future development of personalized treatment with unlimited numbers of autologous cDCs from human iPSCs.

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Gilfillan, Connie B., Sabine Kuhn, Camille Baey, Evelyn J. Hyde, Jianping Yang, Christiane Ruedl, and Franca Ronchese. "Clec9A+ Dendritic Cells Are Not Essential for Antitumor CD8+ T Cell Responses Induced by Poly I:C Immunotherapy." Journal of Immunology 200, no. 8 (March 5, 2018): 2978–86. http://dx.doi.org/10.4049/jimmunol.1701593.

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Gou, Shanshan, Wenwen Liu, Shuai Wang, Guanyu Chen, Zhenzhen Chen, Lu Qiu, Xiuman Zhou, Yahong Wu, Yuanming Qi, and Yanfeng Gao. "Engineered Nanovaccine Targeting Clec9a⁺ Dendritic Cells Remarkably Enhances the Cancer Immunotherapy Effects of STING Agonist." Nano Letters 21, no. 23 (November 15, 2021): 9939–50. http://dx.doi.org/10.1021/acs.nanolett.1c03243.

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Torres, David, Arnaud Köhler, Sandrine Delbauve, Irina Caminschi, Mireille H. Lahoud, Ken Shortman, and Véronique Flamand. "IL-12p40/IL-10 Producing preCD8α/Clec9A+ Dendritic Cells Are Induced in Neonates upon Listeria monocytogenes Infection." PLOS Pathogens 12, no. 4 (April 13, 2016): e1005561. http://dx.doi.org/10.1371/journal.ppat.1005561.

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del Fresno, Carlos, Paula Saz-Leal, Michel Enamorado, Stefanie K. Wculek, Sarai Martínez-Cano, Noelia Blanco-Menéndez, Oliver Schulz, et al. "DNGR-1 in dendritic cells limits tissue damage by dampening neutrophil recruitment." Science 362, no. 6412 (October 18, 2018): 351–56. http://dx.doi.org/10.1126/science.aan8423.

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Host injury triggers feedback mechanisms that limit tissue damage. Conventional type 1 dendritic cells (cDC1s) express dendritic cell natural killer lectin group receptor-1 (DNGR-1), encoded by the gene Clec9a, which senses tissue damage and favors cross-presentation of dead-cell material to CD8+ T cells. Here we find that DNGR-1 additionally reduces host-damaging inflammatory responses induced by sterile and infectious tissue injury in mice. DNGR-1 deficiency leads to exacerbated caerulein-induced necrotizing pancreatitis and increased pathology during systemic Candida albicans infection without affecting fungal burden. This effect is B and T cell–independent and attributable to increased neutrophilia in DNGR-1–deficient settings. Mechanistically, DNGR-1 engagement activates SHP-1 and inhibits MIP-2 (encoded by Cxcl2) production by cDC1s during Candida infection. This consequently restrains neutrophil recruitment and promotes disease tolerance. Thus, DNGR-1–mediated sensing of injury by cDC1s serves as a rheostat for the control of tissue damage, innate immunity, and immunopathology.

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Joffre, Olivier P., David Sancho, Santiago Zelenay, Anna M. Keller, and Caetano Reis e Sousa. "Efficient and versatile manipulation of the peripheral CD4 + T‐cell compartment by antigen targeting to DNGR‐1/CLEC9A." European Journal of Immunology 40, no. 5 (April 29, 2010): 1255–65. http://dx.doi.org/10.1002/eji.201040419.

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Seet, Christopher, Suwen Li, Brent Chick, David Casero, Jocelyn Kim, Eric Gschweng, Ho-Chung Chen, et al. "Notch Signaling Regulates the Differentiation of CLEC9A+ Dendritic Cells (cDC1) From Human and Mouse Hematopoietic Stem/Progenitor Cells." Experimental Hematology 64 (August 2018): S102. http://dx.doi.org/10.1016/j.exphem.2018.06.145.

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Breton, Gaëlle, Jaeyop Lee, Yu Jerry Zhou, Joseph J. Schreiber, Tibor Keler, Sarah Puhr, Niroshana Anandasabapathy, et al. "Circulating precursors of human CD1c+ and CD141+ dendritic cells." Journal of Experimental Medicine 212, no. 3 (February 16, 2015): 401–13. http://dx.doi.org/10.1084/jem.20141441.

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Two subsets of conventional dendritic cells (cDCs) with distinct cell surface markers and functions exist in mouse and human. The two subsets of cDCs are specialized antigen-presenting cells that initiate T cell immunity and tolerance. In the mouse, a migratory cDC precursor (pre-CDC) originates from defined progenitors in the bone marrow (BM). Small numbers of short-lived pre-CDCs travel through the blood and replace cDCs in the peripheral organs, maintaining homeostasis of the highly dynamic cDC pool. However, the identity and distribution of the immediate precursor to human cDCs has not been defined. Using a tissue culture system that supports the development of human DCs, we identify a migratory precursor (hpre-CDC) that exists in human cord blood, BM, blood, and peripheral lymphoid organs. hpre-CDCs differ from premonocytes that are restricted to the BM. In contrast to earlier progenitors with greater developmental potential, the hpre-CDC is restricted to producing CD1c+ and CD141+ Clec9a+ cDCs. Studies in human volunteers demonstrate that hpre-CDCs are a dynamic population that increases in response to levels of circulating Flt3L.

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Sharma, Jyotika, Atul Sharma, Anthony Steichen, Christopher Jondle, Brandilyn Binstock, and Bibhuti Mishra. "Antibacterial and pro-resolving mechanisms in lung diseases: role of C-type lectin receptors (INM2P.430)." Journal of Immunology 192, no. 1_Supplement (May 1, 2014): 56.13. http://dx.doi.org/10.4049/jimmunol.192.supp.56.13.

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Abstract Lower respiratory tract infection with bacteria can lead to sepsis development, a complex immune disorder with systemic hyperinflammation. There are currently no effective therapies for sepsis. To understand the function of specific pulmonary components in regulation of immune responses in this immune disorder, we utilize an acute pulmonary bacterial infection model of Klebsiella pneumoniae (KPn). Nosocomial infections with this opportunistic pathogen account for 5-20% of Gram-negative sepsis cases. C-type lectin receptors (CLRs), expressed mainly by myeloid cells, can shape immune responses in diverse pathological conditions. However, their role in development of pneumonic sepsis is unknown. Our preliminary analysis of a panel of CLRs showed an upregulated expression of two CLRs, Clec4d and Clec4e in the lungs of KPn infected mice. While the wild-type mice were able to resolve a sublethal pneumonic KPn infection, the Clec4d-/- and Clec4e-/- mice displayed increased susceptibility with a progressive increase in bacterial burden, hyperinflammatory response and massive accumulation of neutrophils in lungs. Importantly, we show that coordinated function of Clec4d and Clec4e in neutrophils during bacterial pneumonia, and in a chronic lung disease, leads to control of bacterial growth and hyperinflammation by regulating phagocytosis and efferocytosis (clearance of dead cells). Our studies provide novel insights into regulation of inflammatory derangements in immune disorders.

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Wang, Zhiwei, Ling Ran, Chunxia Chen, Ranran Shi, Yu Dong, Yubing Li, Xiuman Zhou, et al. "Identification of HLA-A2-Restricted Mutant Epitopes from Neoantigens of Esophageal Squamous Cell Carcinoma." Vaccines 9, no. 10 (October 1, 2021): 1118. http://dx.doi.org/10.3390/vaccines9101118.

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Esophageal squamous cell carcinoma (ESCC), one of the deadliest gastrointestinal cancers, has had limited effective therapeutic strategies up to now. Accumulating evidence suggests that effective immunotherapy in cancer patients has been associated with T cells responsive to mutant peptides derived from neoantigens. Here, we selected 35 human leukocyte antigen-A2 (HLA-A2)-restricted mutant (MUT) peptides stemmed from neoantigens of ESCC. Among them, seven mutant peptides had potent binding affinity to HLA-A*0201 molecules and could form a stable peptide/HLA-A*0201 complex. Three mutant peptides (TP53-R267P, NFE2L2-D13N, and PCLO-E4090Q) of those were immunogenic and could induce the cytotoxic T lymphocytes (CTLs) recognizing mutant peptides presented on transfected cells in an HLA-A2-restricted and MUT peptide-specific manner. In addition, the CTL response in immunized HLA-A2.1/Kb transgenic (Tg) mice was enhanced by coupling MUT peptides to peptide WH, a peptide delivery carrier targeting Clec9a+ DCs. Then, the possible binding model conversions between the WT and MUT candidate peptides were analyzed by docking with the pockets of HLA-A*0201 molecule. We therefore propose a novel strategy and epitopes for immunotherapy of ESCC based on neoantigens.

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Gou, Shanshan, Shuai Wang, Wenwen Liu, Guanyu Chen, Dongyang Zhang, Jiangfeng Du, Zhongyi Yan, et al. "Adjuvant-free peptide vaccine targeting Clec9a on dendritic cells can induce robust antitumor immune response through Syk/IL-21 axis." Theranostics 11, no. 15 (2021): 7308–21. http://dx.doi.org/10.7150/thno.56406.

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Lahoud, Mireille H., Fatma Ahmet, Susie Kitsoulis, Soo San Wan, David Vremec, Chin-Nien Lee, Belinda Phipson, et al. "Targeting Antigen to Mouse Dendritic Cells via Clec9A Induces Potent CD4 T Cell Responses Biased toward a Follicular Helper Phenotype." Journal of Immunology 187, no. 2 (June 15, 2011): 842–50. http://dx.doi.org/10.4049/jimmunol.1101176.

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46

Huysamen, Cristal, Janet A. Willment, Kevin M. Dennehy, and Gordon D. Brown. "CLEC9A Is a Novel Activation C-type Lectin-like Receptor Expressed on BDCA3+Dendritic Cells and a Subset of Monocytes." Journal of Biological Chemistry 283, no. 24 (April 11, 2008): 16693–701. http://dx.doi.org/10.1074/jbc.m709923200.

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47

Elleisy, Nagi, Sarah Rohde, Astrid Huth, Nicole Gittel, Änne Glass, Steffen Möller, Georg Lamprecht, Holger Schäffler, and Robert Jaster. "Genetic association analysis of CLEC5A and CLEC7A gene single-nucleotide polymorphisms and Crohn’s disease." World Journal of Gastroenterology 26, no. 18 (May 14, 2020): 2194–202. http://dx.doi.org/10.3748/wjg.v26.i18.2194.

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48

Gulubova, M., M. Hadzhi, L. Hadzhiilieva, D. Chonov, and M. M. Ignatova. "Dendritic Cells and T Cell Subsets in the Development of Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis." Acta Medica Bulgarica 48, no. 3 (October 1, 2021): 49–55. http://dx.doi.org/10.2478/amb-2021-0037.

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Abstract Nonalcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are associated with steatosis, inflammation and fibrosis. Liver dendritic cells (DCs) are usually tolerogenic in the sinusoidal milleu composed of immunosuppressive cytokines. In NAFLD and NASH, DCs become pro-inflammatory and modulate hepatic immune response. Murine liver DCs are three major subtypes: classical (lymphoid) cDC1 or the crosspresenters (CD8α+CD103+), classical (myeloid) cDC2 (CD11b+) and plasmacytoid pDCs (PDCA-1+Siglec-H+) and two additional subtypes or lymphoid + myeloid DCs and NKDCs. Similarly, human liver DCs are three subtypes or CD141+CLEC9A+, CD1c+ (BDCA1+) and pDCs (CD303+BDCA2+). Compared to blood human hepatic DCs are less immature and predominantly induce regulatory T cells (Tregs) and IL-4 secreting T cells (Th2). DCs polarize T cells into different Th types that are in interrelations in NAFLD/NASH. T helper 1 (Th1) (T-bet) cells are associated with adipose tissue inflammation. The differentiation of Th2 (GATA3) cells is induced by IL-4 DCs, increased in NAFLD. Similarly, Th17 cells (RORγt/ RORc) are increased in NAFLD and NASH. Tregs (FoxP3) are increased in the liver in steatosis and Th22 cells (AHR) are elevated in diabetes mellitus 2 (DM2) and adiposity. CD8+ T cells γδT cells and MAIT cells also contribute to liver inflammation.

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49

Poulin, Lionel Franz, Mariolina Salio, Emmanuel Griessinger, Fernando Anjos-Afonso, Ligia Craciun, Ji-Li Chen, Anna M. Keller, et al. "Characterization of human DNGR-1+ BDCA3+ leukocytes as putative equivalents of mouse CD8α+ dendritic cells." Journal of Experimental Medicine 207, no. 6 (May 17, 2010): 1261–71. http://dx.doi.org/10.1084/jem.20092618.

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In mouse, a subset of dendritic cells (DCs) known as CD8α+ DCs has emerged as an important player in the regulation of T cell responses and a promising target in vaccination strategies. However, translation into clinical protocols has been hampered by the failure to identify CD8α+ DCs in humans. Here, we characterize a population of human DCs that expresses DNGR-1 (CLEC9A) and high levels of BDCA3 and resembles mouse CD8α+ DCs in phenotype and function. We describe the presence of such cells in the spleens of humans and humanized mice and report on a protocol to generate them in vitro. Like mouse CD8α+ DCs, human DNGR-1+ BDCA3hi DCs express Necl2, CD207, BATF3, IRF8, and TLR3, but not CD11b, IRF4, TLR7, or (unlike CD8α+ DCs) TLR9. DNGR-1+ BDCA3hi DCs respond to poly I:C and agonists of TLR8, but not of TLR7, and produce interleukin (IL)-12 when given innate and T cell–derived signals. Notably, DNGR-1+ BDCA3+ DCs from in vitro cultures efficiently internalize material from dead cells and can cross-present exogenous antigens to CD8+ T cells upon treatment with poly I:C. The characterization of human DNGR-1+ BDCA3hi DCs and the ability to grow them in vitro opens the door for exploiting this subset in immunotherapy.

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Poulin, Lionel F., Yasmin Reyal, Heli Uronen-Hansson, Barbara U. Schraml, David Sancho, Kenneth M. Murphy, Ulf K. Håkansson, et al. "DNGR-1 is a specific and universal marker of mouse and human Batf3-dependent dendritic cells in lymphoid and nonlymphoid tissues." Blood 119, no. 25 (June 21, 2012): 6052–62. http://dx.doi.org/10.1182/blood-2012-01-406967.

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Abstract Mouse CD8α+ dendritic cells (DCs) in lymphoid organs and CD103+ CD11b− DCs in nonlymphoid tissues share phenotypic and functional similarities, as well as a unique shared developmental dependence on the transcription factor Batf3. Human DCs resembling mouse CD8α+ DCs in phenotype and function have been identified in human blood, spleen, and tonsil. However, it is not clear whether such cells are also present in human nonlymphoid organs, and their equivalence to mouse CD8α+ DC has recently been questioned. Furthermore, the identification of “CD8α+ DC-like” cells across different tissues and species remains problematic because of the lack of a unique marker that can be used to unambiguously define lineage members. Here we show that mouse CD8α+ DCs and CD103+ CD11b− DCs can be defined by shared high expression of DNGR-1 (CLEC9A). We further show that DNGR-1 uniquely marks a CD11b− human DC population present in both lymphoid and nonlymphoid tissues of humans and humanized mice. Finally, we demonstrate that knockdown of Batf3 selectively prevents the development of DNGR-1+ human DCs in vitro. Thus, high expression of DNGR-1 specifically and universally identifies a unique DC subset in mouse and humans. Evolutionarily conserved Batf3 dependence justifies classification of DNGR-1hi DCs as a distinct DC lineage.

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