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Article ; Online: Intratumoural administration of an NKT cell agonist with CpG promotes NKT cell infiltration associated with an enhanced antitumour response and abscopal effect.

Prasit, Kef K / Ferrer-Font, Laura / Burn, Olivia K / Anderson, Regan J / Compton, Benjamin J / Schmidt, Alfonso J / Mayer, Johannes U / Chen, Chun-Jen J / Dasyam, Nathaniel / Ritchie, David S / Godfrey, Dale I / Mattarollo, Stephen R / Dundar, P Rod / Painter, Gavin F / Hermans, Ian F

Oncoimmunology

2022 Volume 11, Issue 1, Page(s) 2081009

Abstract: Intratumoural administration of unmethylated cytosine-phosphate-guanine motifs (CpG) to stimulate toll-like receptor (TLR)-9 has been shown to induce tumour regression in preclinical studies and some efficacy in the clinic. Because activated natural ... ...

Abstract	Intratumoural administration of unmethylated cytosine-phosphate-guanine motifs (CpG) to stimulate toll-like receptor (TLR)-9 has been shown to induce tumour regression in preclinical studies and some efficacy in the clinic. Because activated natural killer T (NKT) cells can cooperate with pattern-recognition via TLRs to improve adaptive immune responses, we assessed the impact of combining a repeated dosing regimen of intratumoural CpG with a single intratumoural dose of the NKT cell agonist α-galactosylceramide (α-GalCer). The combination was superior to CpG alone at inducing regression of established tumours in several murine tumour models, primarily mediated by CD8
MeSH term(s)	Animals ; CD8-Positive T-Lymphocytes ; Cytosine/metabolism ; Cytosine/pharmacology ; Guanine/metabolism ; Guanine/pharmacology ; Interferon-gamma ; Killer Cells, Natural/metabolism ; Lymphocyte Activation ; Mice ; Natural Killer T-Cells/metabolism ; Neoplasms/drug therapy ; Phosphates/metabolism ; Phosphates/pharmacology
Chemical Substances	Phosphates ; Guanine (5Z93L87A1R) ; Interferon-gamma (82115-62-6) ; Cytosine (8J337D1HZY)
Language	English
Publishing date	2022-06-13
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2645309-5
ISSN	2162-402X ; 2162-4011
ISSN (online)	2162-402X
ISSN	2162-4011
DOI	10.1080/2162402X.2022.2081009
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Article ; Online: New ways to turn on NKT cells.

Godfrey, Dale Ian / Rossjohn, Jamie

The Journal of experimental medicine

2011 Volume 208, Issue 6, Page(s) 1121–1125

Abstract: Natural killer T (NKT) cells are CD1d-restricted, lipid antigen-reactive T cells with powerful immunoregulatory potential. The prototypic antigen for NKT cells is a marine sponge-derived glycolipid, α-galactosylceramide (α-GalCer), but this is not ... ...

Abstract	Natural killer T (NKT) cells are CD1d-restricted, lipid antigen-reactive T cells with powerful immunoregulatory potential. The prototypic antigen for NKT cells is a marine sponge-derived glycolipid, α-galactosylceramide (α-GalCer), but this is not normally encountered in the mammalian environment. Thus, there is great interest in the identification of more physiological stimuli for NKT cells, and numerous studies have shown that NKT cells are capable of responding to a range of microbial lipid-based antigens. Two new studies expand our understanding of environmental NKT cell stimuli, with one showing that CD1d-restricted NKT cell antigens are present within common house dust extract (HDE), whereas the other shows that NKT cells can respond to innate stimuli irrespective of the presence of foreign microbial antigens. Collectively, these two investigations indicate that NKT cells are far more likely to encounter foreign antigens, or innate activating signals, than previously recognized, suggesting a more central role for these cells in the immune system.
MeSH term(s)	Animals ; Antigens, CD1d/biosynthesis ; Cytokines/metabolism ; Galactosylceramides/metabolism ; Glycolipids/chemistry ; Humans ; Immune System ; Inflammation ; Lipids/chemistry ; Lymphocyte Activation ; Mice ; Models, Biological ; Natural Killer T-Cells/metabolism
Chemical Substances	Antigens, CD1d ; Cytokines ; Galactosylceramides ; Glycolipids ; Lipids ; alpha-galactosylceramide
Language	English
Publishing date	2011-06-06
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	218343-2
ISSN	1540-9538 ; 0022-1007
ISSN (online)	1540-9538
ISSN	0022-1007
DOI	10.1084/jem.20110983
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Article: IL-21 Modulates Activation of NKT Cells in Patients with Stage IV Malignant Melanoma.

Coquet, Jonathan M / Skak, Kresten / Davis, Ian D / Smyth, Mark J / Godfrey, Dale I

Clinical & translational immunology

2013 Volume 2, Issue 10, Page(s) e6

Abstract: Interleukin-21 (IL-21) is a common γ-chain cytokine produced by T helper and natural killer T (NKT) cells. It has been shown to regulate the response of various lymphocyte subsets including NK, NKT, T and B cells. Owing to its potent anti-tumor function ... ...

Abstract	Interleukin-21 (IL-21) is a common γ-chain cytokine produced by T helper and natural killer T (NKT) cells. It has been shown to regulate the response of various lymphocyte subsets including NK, NKT, T and B cells. Owing to its potent anti-tumor function in preclinical studies and its ability to induce cytotoxicity and interferon-γ (IFN-γ) production in NK and CD8 T cells, recombinant IL-21 (rIL-21) was fast-tracked into early-phase clinical trials of patients with various malignancies. In a phase 2a trial of patients with metastatic melanoma, we analyzed the frequency and function of NKT cells in patients receiving rIL-21. NKT cells were present at a low frequency, but their levels were relatively stable in patients administered rIL-21. Unlike our observations in NK and CD8 T cells, rIL-21 appeared to reduce IFN-γ and TNF production by NKT cells, whereas it enhanced IL-4 production. It also modulated the expression of cell surface markers, specifically on CD4(-) NKT cells. In addition, an increase in CD3(+)CD56(+) NKT-like cells was observed over the course of rIL-21 administration. These results highlight that IL-21 is a potent regulator of NKT cell function in vivo.
Language	English
Publishing date	2013-10-18
Publishing country	Australia
Document type	Journal Article
ZDB-ID	2694482-0
ISSN	2050-0068
ISSN	2050-0068
DOI	10.1038/cti.2013.7
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Article: Induction of a grapevine germin-like protein (VvGLP3) gene is closely linked to the site of Erysiphe necator infection: a possible role in defense?

Godfrey, Dale / Able, Amanda J / Dry, Ian B

Molecular plant-microbe interactions : MPMI

2007 Volume 20, Issue 9, Page(s) 1112–1125

Abstract: Germin-like proteins (GLP) have various proposed roles in plant development and defense. Seven novel GLP cDNA clones were isolated from grapevine (Vitis vinifera cv. Chardonnay). Reverse transcriptase-polymerase chain reaction expression analysis ... ...

Abstract	Germin-like proteins (GLP) have various proposed roles in plant development and defense. Seven novel GLP cDNA clones were isolated from grapevine (Vitis vinifera cv. Chardonnay). Reverse transcriptase-polymerase chain reaction expression analysis revealed that the VvGLP genes exhibit diverse and highly specific patterns of expression in response to a variety of abiotic and biotic treatments, including challenge by Erysiphe necator, Plasmopara viticola, and Botrytis cinerea, suggesting a diversity of roles for each of the GLP family members. Significantly, one of the grapevine GLP genes, VvGLP3, is induced specifically by E. necator infection and expression is closely linked to the site of infection. Subcellular localization of VvGLP3 determined by transient expression of a VvGLP3:GFP fusion construct in onion cells indicated that the recombinant protein was targeted to the cell wall. Recombinant VvGLP3 was successfully expressed in Arabidopsis thaliana and the partially purified recombinant protein was demonstrated to have superoxide dismutase activity. This data has provided an insight into the diverse nature of the GLP family in grapevine and suggests that VvGLP3 may be involved in the defense response against E. necator.
MeSH term(s)	Amino Acid Sequence ; Arabidopsis/genetics ; Arabidopsis/metabolism ; Ascomycota/physiology ; Cloning, Molecular ; Cyclopentanes/metabolism ; Ethylenes/metabolism ; Gene Expression Regulation, Plant ; Molecular Sequence Data ; Multigene Family ; Onions/cytology ; Onions/microbiology ; Oxylipins ; Phylogeny ; Plant Diseases/microbiology ; Plant Leaves/metabolism ; Plant Proteins/chemistry ; Plant Proteins/genetics ; Plant Proteins/metabolism ; Recombinant Proteins ; Salicylic Acid/metabolism ; Signal Transduction ; Superoxide Dismutase/metabolism ; Vitis/genetics ; Vitis/metabolism
Chemical Substances	Cyclopentanes ; Ethylenes ; Oxylipins ; Plant Proteins ; Recombinant Proteins ; jasmonic acid (6RI5N05OWW) ; ethylene (91GW059KN7) ; Superoxide Dismutase (EC 1.15.1.1) ; Salicylic Acid (O414PZ4LPZ)
Language	English
Publishing date	2007-09
Publishing country	United States
Document type	Journal Article
ZDB-ID	743331-1
ISSN	1943-7706 ; 0894-0282
ISSN (online)	1943-7706
ISSN	0894-0282
DOI	10.1094/MPMI-20-9-1112
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Article ; Online: Liver-Resident Memory CD8

Fernandez-Ruiz, Daniel / Ng, Wei Yi / Holz, Lauren E / Ma, Joel Z / Zaid, Ali / Wong, Yik Chun / Lau, Lei Shong / Mollard, Vanessa / Cozijnsen, Anton / Collins, Nicholas / Li, Jessica / Davey, Gayle M / Kato, Yu / Devi, Sapna / Skandari, Roghieh / Pauley, Michael / Manton, Jonathan H / Godfrey, Dale I / Braun, Asolina /

Tay, Szun Szun / Tan, Peck Szee / Bowen, David G / Koch-Nolte, Friedrich / Rissiek, Björn / Carbone, Francis R / Crabb, Brendan S / Lahoud, Mireille / Cockburn, Ian A / Mueller, Scott N / Bertolino, Patrick / McFadden, Geoffrey I / Caminschi, Irina / Heath, William R

Immunity

2019 Volume 51, Issue 4, Page(s) 780

Language	English
Publishing date	2019-10-13
Publishing country	United States
Document type	Published Erratum
ZDB-ID	1217235-2
ISSN	1097-4180 ; 1074-7613
ISSN (online)	1097-4180
ISSN	1074-7613
DOI	10.1016/j.immuni.2019.09.019
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Article ; Online: Enhancing T cell responses and tumour immunity by vaccination with peptides conjugated to a weak NKT cell agonist.

Organic & biomolecular chemistry

2019 Volume 17, Issue 5, Page(s) 1225–1237

Abstract: Activated NKT cells can stimulate antigen-presenting cells leading to enhanced peptide antigen-specific immunity. However, administration of potent NKT cell agonists like α-galactosylceramide (α-GalCer) can be associated with release of high levels of ... ...

Abstract	Activated NKT cells can stimulate antigen-presenting cells leading to enhanced peptide antigen-specific immunity. However, administration of potent NKT cell agonists like α-galactosylceramide (α-GalCer) can be associated with release of high levels of cytokines, and in some situations, hepatotoxicity. Here we show that it is possible to provoke sufficient NKT cell activity to stimulate strong antigen-specific T cell responses without these unwanted effects. This was achieved by chemically conjugating antigenic peptides to α-galactosylphytosphingosine (α-GalPhs), an NKT cell agonist with very weak activity based on structural characterisation and biological assays. Conjugation improved delivery to antigen-presenting cells in vivo, while use of a cathepsin-sensitive linker to release the α-GalPhs and peptide within the same cell promoted strong T cell activation and therapeutic anti-tumour responses in mice. The conjugates activated human NKT cells and enhanced human T cell responses to a viral peptide in vitro. Accordingly, we have demonstrated a means to safely exploit the immunostimulatory properties of NKT cells to enhance T cell activation for virus- and tumour-specific immunity.
MeSH term(s)	Adjuvants, Immunologic ; Animals ; Antigen-Presenting Cells/immunology ; Antigens, CD1d/chemistry ; Cancer Vaccines/administration & dosage ; Cancer Vaccines/immunology ; Chemical and Drug Induced Liver Injury/prevention & control ; Epitopes/chemistry ; Glycolipids/chemistry ; Lymphocyte Activation ; Mice ; Mice, Inbred C57BL ; Natural Killer T-Cells/drug effects ; Natural Killer T-Cells/immunology ; Neoplasms, Experimental/drug therapy ; Neoplasms, Experimental/immunology ; Peptides/administration & dosage ; Peptides/chemistry ; Peptides/immunology
Chemical Substances	Adjuvants, Immunologic ; Antigens, CD1d ; CD1d antigen, mouse ; Cancer Vaccines ; Epitopes ; Glycolipids ; Peptides
Language	English
Publishing date	2019-01-17
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2097583-1
ISSN	1477-0539 ; 1477-0520
ISSN (online)	1477-0539
ISSN	1477-0520
DOI	10.1039/c8ob02982b
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Article ; Online: Invariant NKT cells in hyperplastic skin induce a local immune suppressive environment by IFN-gamma production.

Mattarollo, Stephen R / Rahimpour, Azad / Choyce, Allison / Godfrey, Dale I / Leggatt, Graham R / Frazer, Ian H

Journal of immunology (Baltimore, Md. : 1950)

2010 Volume 184, Issue 3, Page(s) 1242–1250

Abstract: NKT cells can promote or inhibit adaptive immune responses. Cutaneous immunity is tightly regulated by cooperation between innate and adaptive immune processes, but the role of NKT cells in regulating cutaneous immunity is largely unknown. In this study, ...

Abstract	NKT cells can promote or inhibit adaptive immune responses. Cutaneous immunity is tightly regulated by cooperation between innate and adaptive immune processes, but the role of NKT cells in regulating cutaneous immunity is largely unknown. In this study, we show, in a mouse model, that skin-infiltrating CD1d-restricted NKT cells in HPV16-E7 transgenic hyperplastic skin produce IFN-gamma, which can prevent rejection of HPV16-E7-expressing skin grafts. Suppression of graft rejection is associated with the accumulation of CD1d(hi)-expressing CD11c(+)F4/80(hi) myeloid cells in hyperplastic skin. Blockade of CD1d, removal of NKT cells, or local inhibition of IFN-gamma signaling is sufficient to restore immune-mediated graft rejection. Thus, inhibition of NKT cell recruitment or function may enable effective immunity against tumor and viral Ags expressed in epithelial cells.
MeSH term(s)	Animals ; Antigens, CD1d/biosynthesis ; Antigens, CD1d/genetics ; Cells, Cultured ; Chemotaxis, Leukocyte/genetics ; Chemotaxis, Leukocyte/immunology ; Coculture Techniques ; Graft Rejection/immunology ; Graft Rejection/prevention & control ; Graft Rejection/virology ; Human papillomavirus 16/genetics ; Human papillomavirus 16/immunology ; Humans ; Hyperplasia ; Immune Tolerance/genetics ; Interferon-gamma/biosynthesis ; Interferon-gamma/deficiency ; Interferon-gamma/physiology ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Mice, Transgenic ; Natural Killer T-Cells/immunology ; Natural Killer T-Cells/metabolism ; Natural Killer T-Cells/transplantation ; Oncogene Proteins, Viral/genetics ; Papillomavirus E7 Proteins ; Skin/immunology ; Skin/metabolism ; Skin/pathology ; Skin Transplantation/immunology ; Skin Transplantation/pathology ; Tissue Culture Techniques
Chemical Substances	Antigens, CD1d ; Oncogene Proteins, Viral ; Papillomavirus E7 Proteins ; oncogene protein E7, Human papillomavirus type 16 ; Interferon-gamma (82115-62-6)
Language	English
Publishing date	2010-02-01
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	3056-9
ISSN	1550-6606 ; 0022-1767 ; 1048-3233 ; 1047-7381
ISSN (online)	1550-6606
ISSN	0022-1767 ; 1048-3233 ; 1047-7381
DOI	10.4049/jimmunol.0902191
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Article ; Online: Glycolipid-peptide vaccination induces liver-resident memory CD8

Holz, Lauren E / Chua, Yu Cheng / de Menezes, Maria N / Anderson, Regan J / Draper, Sarah L / Compton, Benjamin J / Chan, Susanna T S / Mathew, Juby / Li, Jasmine / Kedzierski, Lukasz / Wang, Zhongfang / Beattie, Lynette / Enders, Matthias H / Ghilas, Sonia / May, Rose / Steiner, Thiago M / Lange, Joshua / Fernandez-Ruiz, Daniel / Valencia-Hernandez, Ana Maria /

Osmond, Taryn L / Farrand, Kathryn J / Seneviratna, Rebecca / Almeida, Catarina F / Tullett, Kirsteen M / Bertolino, Patrick / Bowen, David G / Cozijnsen, Anton / Mollard, Vanessa / McFadden, Geoffrey I / Caminschi, Irina / Lahoud, Mireille H / Kedzierska, Katherine / Turner, Stephen J / Godfrey, Dale I / Hermans, Ian F / Painter, Gavin F / Heath, William R

Science immunology

2020 Volume 5, Issue 48

Abstract: Liver resident-memory ... ...

Abstract	Liver resident-memory CD8
MeSH term(s)	Animals ; CD8-Positive T-Lymphocytes/immunology ; CD8-Positive T-Lymphocytes/pathology ; Glycolipids/immunology ; Liver/immunology ; Liver/pathology ; Malaria/immunology ; Malaria/pathology ; Malaria Vaccines/immunology ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Peptides/immunology ; Vaccination
Chemical Substances	Glycolipids ; Malaria Vaccines ; Peptides
Language	English
Publishing date	2020-06-26
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	2470-9468
ISSN (online)	2470-9468
DOI	10.1126/sciimmunol.aaz8035
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Article ; Online: Augmenting Influenza-Specific T Cell Memory Generation with a Natural Killer T Cell-Dependent Glycolipid-Peptide Vaccine.

ACS chemical biology

2017 Volume 12, Issue 11, Page(s) 2898–2905

Abstract: The development of a universal vaccine for influenza A virus (IAV) that does not require seasonal modification is a long-standing health goal, particularly in the context of the increasing threat of new global pandemics. Vaccines that specifically induce ...

Abstract	The development of a universal vaccine for influenza A virus (IAV) that does not require seasonal modification is a long-standing health goal, particularly in the context of the increasing threat of new global pandemics. Vaccines that specifically induce T cell responses are of considerable interest because they can target viral proteins that are more likely to be shared between different virus strains and subtypes and hence provide effective cross-reactive IAV immunity. From a practical perspective, such vaccines should induce T cell responses with long-lasting memory, while also being simple to manufacture and cost-effective. Here we describe the synthesis and evaluation of a vaccine platform based on solid phase peptide synthesis and bio-orthogonal conjugation methodologies. The chemical approach involves covalently attaching synthetic long peptides from a virus-associated protein to a powerful adjuvant molecule, α-galactosylceramide (α-GalCer). Strain-promoted azide-alkyne cycloaddition is used as a simple and efficient method for conjugation, and pseudoproline methodology is used to increase the efficiency of the peptide synthesis. α-GalCer is a glycolipid that stimulates NKT cells, a population of lymphoid-resident immune cells that can provide potent stimulatory signals to antigen-presenting cells engaged in driving proliferation and differentiation of peptide-specific T cells. When used in mice, the vaccine induced T cell responses that provided effective prophylactic protection against IAV infection, with the speed of viral clearance greater than that seen from previous viral exposure. These findings are significant because the vaccines are highly defined, quick to synthesize, and easily characterized and are therefore appropriate for large scale affordable manufacture.
Language	English
Publishing date	2017-11-17
Publishing country	United States
Document type	Journal Article
ISSN	1554-8937
ISSN (online)	1554-8937
DOI	10.1021/acschembio.7b00845
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Article ; Online: A non-canonical function of Ezh2 preserves immune homeostasis.

Vasanthakumar, Ajithkumar / Xu, Dakang / Lun, Aaron Tl / Kueh, Andrew J / van Gisbergen, Klaas Pjm / Iannarella, Nadia / Li, Xiaofang / Yu, Liang / Wang, Die / Williams, Bryan Rg / Lee, Stanley Cw / Majewski, Ian J / Godfrey, Dale I / Smyth, Gordon K / Alexander, Warren S / Herold, Marco J / Kallies, Axel / Nutt, Stephen L / Allan, Rhys S

EMBO reports

2017 Volume 18, Issue 4, Page(s) 619–631

Abstract: Enhancer of zeste 2 (Ezh2) mainly methylates lysine 27 of histone-H3 (H3K27me3) as part of the polycomb repressive complex 2 (PRC2) together with Suz12 and Eed. However, Ezh2 can also modify non-histone substrates, although it is unclear whether this ... ...

Abstract	Enhancer of zeste 2 (Ezh2) mainly methylates lysine 27 of histone-H3 (H3K27me3) as part of the polycomb repressive complex 2 (PRC2) together with Suz12 and Eed. However, Ezh2 can also modify non-histone substrates, although it is unclear whether this mechanism has a role during development. Here, we present evidence for a chromatin-independent role of Ezh2 during T-cell development and immune homeostasis. T-cell-specific depletion of Ezh2 induces a pronounced expansion of natural killer T (NKT) cells, although Ezh2-deficient T cells maintain normal levels of H3K27me3. In contrast, removal of Suz12 or Eed destabilizes canonical PRC2 function and ablates NKT cell development completely. We further show that Ezh2 directly methylates the NKT cell lineage defining transcription factor PLZF, leading to its ubiquitination and subsequent degradation. Sustained PLZF expression in Ezh2-deficient mice is associated with the expansion of a subset of NKT cells that cause immune perturbation. Taken together, we have identified a chromatin-independent function of Ezh2 that impacts on the development of the immune system.
MeSH term(s)	Animals ; Cell Differentiation ; Cell Line ; Enhancer of Zeste Homolog 2 Protein/genetics ; Enhancer of Zeste Homolog 2 Protein/metabolism ; Gene Expression ; Homeostasis ; Humans ; Immunity/genetics ; Kruppel-Like Transcription Factors/genetics ; Kruppel-Like Transcription Factors/metabolism ; Methylation ; Mice ; Mice, Knockout ; Natural Killer T-Cells/immunology ; Natural Killer T-Cells/metabolism ; Promyelocytic Leukemia Zinc Finger Protein ; Protein Binding ; Proteolysis ; Receptors, Antigen, T-Cell, alpha-beta/genetics ; Receptors, Antigen, T-Cell, alpha-beta/metabolism ; T-Lymphocyte Subsets/immunology ; T-Lymphocyte Subsets/metabolism ; Thymocytes/cytology ; Thymocytes/immunology ; Thymocytes/metabolism
Chemical Substances	Kruppel-Like Transcription Factors ; Promyelocytic Leukemia Zinc Finger Protein ; Receptors, Antigen, T-Cell, alpha-beta ; Zbtb16 protein, mouse ; Enhancer of Zeste Homolog 2 Protein (EC 2.1.1.43)
Language	English
Publishing date	2017-02-21
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2020896-0
ISSN	1469-3178 ; 1469-221X
ISSN (online)	1469-3178
ISSN	1469-221X
DOI	10.15252/embr.201643237
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