Immunology
- Protection and mechanism of action of a novel human respiratory syncytial virus vaccine candidate based on the extracellular domain of small hydrophobic protein
- Bert Schepens*,1,2,
- Koen Sedeyn1,2,
- Liesbeth Vande Ginste1,2,
- Sarah De Baets1,2,
- Michael Schotsaert1,2,
- Kenny Roose1,2,
- Lieselot Houspie3,
- Marc Van Ranst3,
- Brian Gilbert4,
- Nico van Rooijen5,
- Walter Fiers1,2,
- Pedro Piedra4,6 and
- Xavier Saelens*,1,2
- 1VIB Inflammation Research Center, Ghent, Belgium
- 2Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
- 3Laboratory of Clinical Virology, Rega Institute for Medical Research KU Leuven, Leuven, Belgium
- 4Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX, USA
- 5Department of Molecular Cell Biology, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
- 6Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA
- ↵*
Corresponding author. Tel: +32 9 33 13 624; Fax: +32 9 221 76 73; E‐mail: bert.schepens{at}irc.vib-ugent.be
Corresponding author. Tel: +32 9 33 13 620; Fax: +32 9 221 76 73; E‐mail: xavier.saelens{at}irc.vib-ugent.be
Vaccination with the ectodomain of the Small Hydrophobic Protein (SHe) controls pulmonary replication of Human Respiratory Syncytial Virus (HRSV). Combining SHe‐based antigens to vaccines that aim at inducing neutralizing antibodies could further improve immunoprotection against HRSV.
Synopsis
Vaccination with the ectodomain of the small hydrophobic protein (SHe) controls pulmonary replication of human respiratory syncytial virus (HRSV). Combining SHe‐based antigens to vaccines that aim at inducing neutralizing antibodies could further improve immunoprotection against HRSV.
SHe‐based vaccination induces SHe‐specific non‐neutralizing antibodies that reduce viral replication in two animal models.
Pulmonary HRSV replication and associated morbidity are reduced by SHe‐specific immune serum.
The reduction of viral replication by SHe‐specific antibodies strongly depends on Fcγ receptor I and/or III and at least partially on alveolar macrophages.
HRSV‐infected cells, but not virions, are readily recognized by SHe‐specific antibodies.
EMBO Mol Med (2014) 6:1436–1454
- Received February 24, 2014.
- Revision received September 8, 2014.
- Accepted September 9, 2014.
- © 2014 The Authors. Published under the terms of the CC BY 4.0 license
This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
- TLR8 signaling enhances tumor immunity by preventing tumor‐induced T‐cell senescence
- Jian Ye1,
- Chunling Ma1,2,
- Eddy C Hsueh3,
- Jie Dou1,
- Wei Mo1,
- Shuai Liu1,
- Bing Han1,
- Yi Huang1,
- Yanping Zhang3,
- Mark A Varvares4,
- Daniel F Hoft1 and
- Guangyong Peng*,1
- 1Department of Internal Medicine, Division of Infectious Diseases, Allergy & Immunology, Saint Louis University School of Medicine, Saint Louis, MO, USA
- 2Department of Laboratory Medicine, Women & Children's Health Care Hospital of Linyi, Linyi, China
- 3Department of Surgery, Division of General Surgery, Saint Louis University School of Medicine, Saint Louis, MO, USA
- 4Department of Otolaryngology‐Head and Neck Surgery, Saint Louis University School of Medicine, Saint Louis, MO, USA
- ↵*Corresponding author. Tel: +1 314 977 9064; Fax: +1 314 771 3816; E‐mail: gpeng{at}slu.edu
This study identifies the induction of T‐cell senescence as a novel mechanism utilized by human tumor cells to induce immune suppression, and provides a new strategy using TLR8 ligands to reverse tumor immunosuppressive effects for tumor immunotherapy.
Synopsis
This study identifies the induction of T‐cell senescence as a novel mechanism utilized by human tumor cells to induce immune suppression, and provides a new strategy using TLR8 ligands to reverse tumor immunosuppressive effects for tumor immunotherapy.
Tumor cells convert naïve/effector T cells into senescent T cells with potent suppressive function.
Tumor‐derived cAMP is responsible for the tumor cell‐induced T‐cell senescence.
cAMP is directly transferred from tumor cells to targeted T cells through gap junctions inducing PKA‐LCK inhibitory signaling and senescence in T cells.
TLR8 signaling reverses tumor‐induced T‐cell senescence via down‐regulation of cAMP in tumor cells.
Activation of TLR8 signaling in tumor cells prevents tumor‐specific T‐cell senescence and enhances anti‐tumor immunity.
EMBO Mol Med (2014) 6:1294–1311
- Received January 29, 2014.
- Revision received August 12, 2014.
- Accepted August 13, 2014.
- © 2014 The Authors. Published under the terms of the CC BY 4.0 license
This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
- Specific roles for dendritic cell subsets during initiation and progression of psoriasis
- Elisabeth Glitzner1,
- Ana Korosec1,
- Patrick M Brunner2,
- Barbara Drobits1,
- Nicole Amberg1,
- Helia B Schonthaler3,
- Tamara Kopp2,
- Erwin F Wagner3,
- Georg Stingl2,
- Martin Holcmann1 and
- Maria Sibilia*,1
- 1Department of Medicine I, Comprehensive Cancer Center Institute of Cancer Research Medical University of Vienna, Vienna, Austria
- 2Department of Dermatology, Division of Immunology, Allergy and Infectious Diseases, Medical University of Vienna, Vienna, Austria
- 3BBVA Foundation–CNIO Cancer Cell Biology Programme Spanish National Cancer Research Centre (CNIO), Madrid, Spain
- ↵*Corresponding author. Tel: +43 140160 57502; Fax: +43 140160 957502; E‐mail: maria.sibilia{at}meduniwien.ac.at
Resident epidermal LCs, which are gradually lost from the epidermis in active disease phase psoriasis, are responsible for maintaining a suppressive skin environment by balancing the anti‐inflammatory IL‐10 and pro‐inflammatory IL‐23 axis.
Synopsis
Resident epidermal LCs, which are gradually lost from the epidermis in active disease phase psoriasis, are responsible for maintaining a suppressive skin environment by balancing the anti‐inflammatory IL‐10 and pro‐inflammatory IL‐23 axis.
Langerhans cells (LCs) are severely reduced and plasmacytoid DCs (pDCs) are increased in human psoriasis as well as in mouse models of psoriasis
Depletion of pDCs in mice prior to psoriasis induction results in disease amelioration whereas depletion during active disease has no effect
Depletion of LCs during active psoriasis results in disease aggravation whereas depletion before disease initiation has no effect
The anti‐inflammatory role of LCs is mediated by direct release of the immunosuppressive cytokine IL‐10 and by preventing excessive IL‐23 accumulation in the skin
pDC depletion results in reduced IL‐23 levels and therapeutic inhibition of IL‐23 receptor ameliorates disease symptoms
EMBO Mol Med (2014) 6:1312–1327
- Received March 27, 2014.
- Revision received August 12, 2014.
- Accepted August 15, 2014.
- © 2014 The Authors. Published under the terms of the CC BY 4.0 license
This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
- Murine Langerin+ dermal dendritic cells prime CD8+ T cells while Langerhans cells induce cross‐tolerance
- Vincent Flacher1,24,
- Christoph H Tripp1,2,
- David G Mairhofer1,
- Ralph M Steinman3,
- Patrizia Stoitzner*,1,†,
- Juliana Idoyaga35 and
- Nikolaus Romani*,1,2,†
- 1Department of Dermatology and Venereology, Innsbruck Medical University, Innsbruck, Austria
- 2Oncotyrol Center for Personalized Cancer Medicine, Innsbruck, Austria
- 3Laboratory of Cellular Physiology and Immunology and Chris Browne Center for Immunology and Immune Diseases, The Rockefeller University, New York, NY, USA
- 4Laboratory of Immunopathology and Therapeutic Chemistry/Laboratory of Excellence MEDALIS, CNRS UPR3572 Institut de Biologie Moléculaire et Cellulaire, Strasbourg, France
- 5Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA
- ↵*
Corresponding author. Tel: +43 512 504 28559; Fax: +43 512 504 67 28559; E‐mail: nikolaus.romani{at}i-med.ac.at
Corresponding author. Tel: +43 512 504 23016; Fax: +43 512 504 67 28592; E‐mail: patrizia.stoitzner{at}i-med.ac.at
-
↵† These authors contributed equally to this work.
The properties of two murine skin antigen‐presenting dendritic cell (DC) subsets were investigated in vivo. Following adjuvanted OVA‐immunization, functional differences were found between the DC subsets that may bear translational relevance for vaccination in the skin.
Synopsis
The properties of two murine skin antigen‐presenting dendritic cell (DC) subsets were investigated in vivo. Following adjuvanted OVA‐immunization, functional differences were found between the DC subsets that may bear translational relevance for vaccination in the skin.
Both Langerin+ dermal DCs and epidermal Langerhans cells (LC) can present exogenous antigen to CD8+ T cells.
Langerin+ dermal DCs prime long‐lasting cytotoxic responses, while cross‐presentation by LCs negatively influences CD8+ T‐cell priming.
Specific adjuvants can be used to independently harness the different potential of distinct DC subsets simultaneously targeted by an antigen.
Treatment of skin with imiquimod, an agonist of TLR7, does not result in potent immune responses when the antigen is targeted to Langerin, thereby relativizing the paradigm stating that mature DCs always promote immunity.
EMBO Mol Med (2014) 6:1191–1204
- Received July 12, 2013.
- Revision received July 4, 2014.
- Accepted July 8, 2014.
- © 2014 The Authors. Published under the terms of the CC BY 4.0 license
This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
- Targeting macrophage Histone deacetylase 3 stabilizes atherosclerotic lesions
- Marten A Hoeksema1,
- Marion JJ Gijbels1,2,3,
- Jan Van den Bossche1,
- Saskia van der Velden1,
- Ayestha Sijm1,
- Annette E Neele1,
- Tom Seijkens1,
- J Lauran Stöger1,
- Svenja Meiler1,
- Marieke CS Boshuizen1,
- Geesje M Dallinga‐Thie4,
- Johannes HM Levels4,
- Louis Boon5,
- Shannon E Mullican6,
- Nathanael J Spann7,
- Jack P Cleutjens2,
- Chris K Glass7,
- Mitchell A Lazar6,
- Carlie JM de Vries1,
- Erik AL Biessen2,
- Mat JAP Daemen8,
- Esther Lutgens1,9 and
- Menno PJ de Winther*,1
- 1Department of Medical Biochemistry, Experimental Vascular Biology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
- 2Department of Pathology, Maastricht University, Maastricht, The Netherlands
- 3Department of Molecular Genetics, Maastricht University, Maastricht, The Netherlands
- 4Department of Vascular and Experimental Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
- 5Bioceros BV, Utrecht, The Netherlands
- 6Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA
- 7Department of Cellular and Molecular Medicine, University of California, San Diego, CA, USA
- 8Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
- 9Institute for Cardiovascular Prevention (IPEK), Ludwig Maximilian's University, Munich, Germany
- ↵*Corresponding author. Tel: +31 20 5666762; E‐mail: m.dewinther{at}amc.uva.nl
Hdac3 is shown to be an important modulator of the fibrotic phenotype of macrophages in atherosclerosis and, in humans, the expression of Hdac3 is linked to plaque vulnerability to rupture.
Synopsis
Hdac3 is shown to be an important modulator of the fibrotic phenotype of macrophages in atherosclerosis and, in humans, the expression of Hdac3 is linked to plaque vulnerability to rupture.
Myeloid Hdac3 deficiency promotes collagen deposition in atherosclerosis
Macrophage Hdac3 deletion enhances TGF‐β secretion thereby increasing collagen production by vascular smooth muscle cells and results in improved lipid handling by de‐repression of PPARγ and LXR responses
In humans, Hdac3 is upregulated in ruptured atherosclerotic lesions and is associated with inflammatory macrophages
Fine‐tuning of the macrophage phenotype by altering the epigenetic landscape can be applied to affect atherosclerotic disease outcome
EMBO Mol Med (2014) 6:1124–1132
- Received April 14, 2014.
- Revision received June 6, 2014.
- Accepted June 10, 2014.
- © 2014 The Authors. Published under the terms of the CC BY 4.0 license
This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
- Macrophages and β‐cells are responsible for CXCR2‐mediated neutrophil infiltration of the pancreas during autoimmune diabetes
- 1Institut National de la Santé et de la Recherche Médicale (INSERM), U1151, Necker‐Enfants Malades Institute (INEM) Necker Hospital, Paris, France
- 2Sorbonne Paris Cité, Université Paris Descartes, Paris, France
- 3Institut National de la Santé et de la Recherche Médicale (INSERM), U1016, Cochin Institute Cochin Hospital, Paris, France
- 4Laboratoire d'Excellence INFLAMEX, Paris, France
- ↵*Corresponding author. Tel: +33 1 44 49 50 69; E‐mail: julien.diana{at}inserm.fr
This study reveals the interaction between inflammatory macrophages and β‐cells leading to the recruitment of diabetogenic neutrophils in the pancreas of neonatal mice via CXCR2/CXCR2 ligands. Inhibition of CXCR2 reduces the diabetogenic T‐cell response, insulitis, and incidence of diabetes.
Synopsis
This study reveals the interaction between inflammatory macrophages and β‐cells leading to the recruitment of diabetogenic neutrophils in the pancreas of neonatal mice via CXCR2/CXCR2 ligands. Inhibition of CXCR2 reduces the diabetogenic T‐cell response, insulitis, and incidence of diabetes.
In young NOD mice, CXCR2+‐neutrophils are recruited from the blood into the pancreatic islets and not in the two non‐diabetes prone C57BL/6 and BALB/c mice.
The two CXCR2 ligands, CXCL1 and CXCL2, are secreted in the pancreatic islets from the young and not from the adult NOD mice or the two non‐diabetes prone mice.
The pancreatic β‐cells are the main source of CXCL1 and CXCL2 in the pancreatic islets of young NOD mice.
The production of CXCL1 and CXCL2 by the β‐cells is induced by IL‐1b‐producing macrophages infiltrating the pancreatic islets of young NOD mice.
The early blockage of neutrophil recruitment using CXCR2 antagonist reduces the insulitis, the effector activity of diabetogenic CD8 T cells, and the development of autoimmune diabetes in NOD mice.
EMBO Mol Med (2014) 6:1090–1104
- Received April 7, 2014.
- Revision received May 27, 2014.
- Accepted May 28, 2014.
- © 2014 The Authors. Published under the terms of the CC BY 4.0 license
This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
- IgE actions on CD4+ T cells, mast cells, and macrophages participate in the pathogenesis of experimental abdominal aortic aneurysms
- Jing Wang1,
- Jes S Lindholt2,
- Galina K Sukhova1,
- Michael A Shi1,
- Mingcan Xia3,
- Han Chen1,4,
- Meixiang Xiang4,
- Aina He1,
- Yi Wang1,
- Na Xiong3,
- Peter Libby1,
- Jian‐An Wang*,4 and
- Guo‐Ping Shi*,1
- 1Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
- 2Department of Cardiovascular and Thoracic Surgery, Elitary Research Centre of Individualized Medicine in Arterial Diseases, University Hospital of Odense, Odense, Denmark
- 3Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA, USA
- 4Cardiovascular Key Lab of Zhejiang Province, Department of Cardiology, College of Medicine, The Second Affiliated Hospital Zhejiang University, Hangzhou, China
- ↵*
Corresponding author. Tel: +1 617 525 4358; Fax: +1 617 525 4380; E‐mail: gshi{at}rics.bwh.harvard.edu
Corresponding author. Tel: +86 138 057 86328; Fax: +86 571 87022776; E‐mail: wja{at}zju.edu.cn
This study demonstrates the pathologic role of IgE and its high affinity receptor FcεR1 in AAAs by activating MCs, macrophages but also CD4 and CD8 T cells and suggests anti‐IgE antibodies as future putative therapeutics for treatment.
Synopsis
This study demonstrates the pathologic role of IgE and its high affinity receptor FcεR1 in AAAs by activating MCs, macrophages but also CD4 and CD8 T cells and suggests anti‐IgE antibodies as future putative therapeutics for treatment.
IgE is expressed in MCs, macrophages, and CD4+ and CD8+ T cells in human AAA lesions.
Genetic depletion of IgE high affinity receptor FcεR1 protects mice from AAA formation.
Reduced AAAs in FcεR1‐deficient mice can be reversed to different extent after mice receiving donor MCs, macrophages, and CD4+ T cells from wild‐type mice but not those from FcεR1‐deficient mice.
Interruption of IgE‐FcεR1 interaction with an anti‐IgE antibody achieves similar AAA inhibitory effect to that from FcεR1‐deficient mice.
EMBO Mol Med (2014) 6: 952–969
- Received December 31, 2013.
- Revision received May 21, 2014.
- Accepted May 22, 2014.
- © 2014 The Authors. Published under the terms of the CC BY 4.0 license
This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
- S100A1 is released from ischemic cardiomyocytes and signals myocardial damage via Toll‐like receptor 4
- David Rohde1,
- Christoph Schön1,
- Melanie Boerries2,3,
- Ieva Didrihsone1,
- Julia Ritterhoff1,
- Katharina F Kubatzky4,
- Mirko Völkers1,
- Nicole Herzog1,
- Mona Mähler1,
- James N Tsoporis5,
- Thomas G Parker5,
- Björn Linke6,
- Evangelos Giannitsis1,
- Erhe Gao7,
- Karsten Peppel7,
- Hugo A Katus1,8 and
- Patrick Most*,1,7,8
- 1Section of Molecular and Translational Cardiology, Department of Internal Medicine III, Heidelberg University Hospital Heidelberg University, Heidelberg, Germany
- 2Institute of Molecular Medicine and Cell Research, Freiburg University, Freiburg, Germany
- 3German Consortium for Translational Cancer Research (DKTK), Partner site Freiburg German Cancer Research Center (DKFZ), Heidelberg, Germany
- 4Division for Microbiology and Hygiene, Department of Infectious Diseases, Heidelberg University Hospital Heidelberg University, Heidelberg, Germany
- 5Division of Cardiology, Department of Medicine, Keenan Research Centre Li Ka Shing Knowledge Institute St. Michael's Hospital University of Toronto, Ontario, Canada
- 6Division of Immunogenetics, Tumor Immunology Program, German Cancer Research Center (DKFZ), Heidelberg, Germany
- 7Center for Translational Medicine, Department of Medicine, Thomas Jefferson University, Philadelphia, PA, USA
- 8German Centre for Cardiovascular Research (DZHK), Partner site Heidelberg/Mannheim Heidelberg University Hospital Heidelberg University, Heidelberg, Germany
- ↵*Corresponding author. Tel: +49 6221 568900; Fax: +49 6221 567632; E‐mail: patrick.most{at}med.uni-heidelberg.de
S100A1 is a novel alarmin found released from ischemic cardiomyocytes of both patients and mice during heart attacks. Internalized by cardiac fibroblasts, S100A1 transiently signals via TLR4 to induce an immunomodulatory beneficial response and an anti‐fibrotic phenotype.
Synopsis
S100A1 is a novel alarmin found released from ischemic cardiomyocytes of both patients and mice during heart attacks. Internalized by cardiac fibroblasts, S100A1 transiently signals via TLR4 to induce an immunomodulatory beneficial response and an anti‐fibrotic phenotype.
In patients with acute ST‐segment elevation myocardial infarction (STEMI), significantly elevated serum levels of S100A1 protein were found when compared to control patients without acute myocardial infarction (n = 12 patients in each group).
In C57B/6 mice, S100A1 from damaged cardiomyocytes was exclusively internalized by surrounding cardiac fibroblasts via fluid endocytosis.
In vitro, endocytosed S100A1 transiently activated intracellular Toll‐like receptor 4 (TLR4) and evoked an immunomodulatory and anti‐fibrotic phenotype transition of cardiac fibroblasts.
In mice, antibody‐mediated neutralization of S100A1 during experimental myocardial infarction resulted in impaired infarct healing and significantly worsened heart function.
EMBO Mol Med (2014) 6: 778–794
- Received September 17, 2013.
- Revision received March 27, 2014.
- Accepted April 15, 2014.
- © 2014 The Authors. Published under the terms of the CC BY 4.0 license
This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
- Vaccines for the 21st century
- ↵*Corresponding author. Tel: +39 0577 245102; Fax: +39 0577 243564; E‐mail: ennio.de_gregorio{at}novartis.com
This novel review of the host‐pathogen interactions series highlights the scientific and practical challenges facing vaccine development: starting with a historical perspective, the authors illustrate the current novel technologies with a focus on vaccines for infectious diseases.
EMBO Mol Med (2014) 6: 708–720
- Received January 17, 2014.
- Revision received March 20, 2014.
- Accepted April 7, 2014.
- © 2014 The Authors. Published under the terms of the CC BY 4.0 license
This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
- Monocyte‐derived dendritic cells identified as booster of T follicular helper cell differentiation
- Simon Fillatreau (simonfillatreau{at}googlemail.com) 1
Adjuvants play an essential role in the induction of acquired immunity upon vaccination with protein antigen. In this issue of EMBO Molecular Medicine, a classical type of adjuvant made of DNA oligonucleotide containing CpG motifs, which has already been used in humans, is shown to boost humoral immunity primarily by acting on monocyte‐derived dendritic cells. This study provides novel insight on the mode of action of adjuvant targeting Toll‐like receptors.
See also: S Chakarov & N Fazilleau (May 2014)
In this issue of EMBO Molecular Medicine, an adjuvant containing CpG motifs and thereby targeting Toll‐like receptors is shown to boost humoral immunity by primarily acting on monocyte‐derived dendritic cells.
- © 2014 The Author. Published under the terms of the CC BY 4.0 license
This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
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