Immunology
- Myc or no Myc, that is the question
The transcription factor c‐MYC functions as the master transcription factor for establishing highly active metabolic states in proliferating cells. c‐Myc is essential for rapid proliferation of normal cells and has causal relationship with many cancers, including leukemia and lymphoma. While the expression of c‐MYC can be aberrantly driven by genetic abnormalities, such as chromosomal translocations directly involving the MYC locus or mutations of its upstream regulators, how c‐MYC expression is induced and amplified in normal lymphocytes in response to antigen stimulation remains elusive. In this issue of The EMBO Journal, Preston et al (2015) report how c‐MYC is selectively induced and amplified in the antigen‐specific T cells that undergo massive clonal expansion for host protection against pathogen infection.
See also: GC Preston et al (August 2015)
Recent work illustrates how c‐MYC is selectively induced and amplified in antigen‐specific T cells that undergo massive clonal expansion for host protection against pathogen infection.
- © 2015 The Authors
- Single cell tuning of Myc expression by antigen receptor signal strength and interleukin‐2 in T lymphocytes
- Gavin C Preston1,
- Linda V Sinclair1,
- Aneesa Kaskar1,2,
- Jens L Hukelmann1,2,
- Maria N Navarro1,3,
- Isabel Ferrero4,
- H Robson MacDonald4,
- Victoria H Cowling2 and
- Doreen A Cantrell*,1
- 1Department of Cell Signalling & Immunology, College of Life Sciences University of Dundee, Dundee, UK
- 2Centre for Gene Regulation and Expression, College of Life Sciences University of Dundee, Dundee, UK
- 3Instituto Investigación Sanitaria/Hospital Universitario de la Princesa Universidad Autónoma de Madrid, Madrid, Spain
- 4Ludwig Center for Cancer Research of the University of Lausanne, Epalinges, Switzerland
- ↵*Corresponding author. Tel: +44 1382 385156; E‐mail: d.a.cantrell{at}dundee.ac.uk
A combination of digital and analogue processes allows tight control of Myc expression at the population and single cell level during T lymphocyte immune responses and matches Myc expression to biosynthetic demands.
Synopsis
A combination of digital and analogue processes allows tight control of Myc expression at the population and single cell level during T lymphocyte immune responses and matches Myc expression to biosynthetic demands.
The T cell antigen receptor operates an essential on/off switch for Myc expression. The strength of the antigen stimulus determines the frequency of immune‐activated T cells that express Myc.
Myc protein has a very short half‐life in activated T cells because it is constantly phosphorylated by glycogen synthase kinase 3 (GSK3) and targeted for proteasomal degradation.
The constant high level of Myc proteolysis means Myc protein levels can only be sustained in T cells that have high rates of amino acid uptake and protein synthesis.
The post‐transcriptional control of Myc protein is used by pro‐inflammatory cytokines such as interleukin‐2 to fine‐tune Myc levels in individual T cells.
The fine‐tuning of Myc levels in individual T cells is shown to be important for a key aspect of T cell metabolism: the regulated uptake of transferrin that ensures immune‐activated T cells have sufficient iron.
The EMBO Journal (2015) 34: 2008–2024
- Received October 7, 2014.
- Revision received May 15, 2015.
- Accepted May 18, 2015.
- © 2015 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.
- The wound inflammatory response exacerbates growth of pre‐neoplastic cells and progression to cancer
- Nicole Antonio1,†,
- Marie Louise Bønnelykke‐Behrndtz2,3,†,
- Laura Chloe Ward4,†,
- John Collin4,
- Ib Jarle Christensen5,
- Torben Steiniche6,7,
- Henrik Schmidt*,7,8,
- Yi Feng*,9 and
- Paul Martin*,1,4,10
- 1School of Biochemistry, University of Bristol, Bristol, UK
- 2Department of Experimental Clinical Oncology, Aarhus University, Aarhus, Denmark
- 3Department of Plastic and Reconstructive Surgery, Aarhus University, Aarhus, Denmark
- 4School of Physiology and Pharmacology, University of Bristol, Bristol, UK
- 5Department of Public Health, University of Copenhagen, Copenhagen, Denmark
- 6Department of Pathology, Aarhus University, Aarhus, Denmark
- 7Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
- 8Department of Oncology, Aarhus University, Aarhus, Denmark
- 9MRC Centre for Inflammation Research, University of Edinburgh, Edinburgh, UK
- 10School of Medicine, University of Cardiff, Cardiff, UK
- ↵*
Corresponding author. Tel: +45 7846 1682; E‐mail: henrschm{at}rm.dk
Corresponding author. Tel: +44 131 242 6685; E‐mail: yi.feng{at}ed.ac.uk
Corresponding author. Tel: +44 117 331 2298; E‐mail: paul.martin{at}bristol.ac.uk
↵† These authors contributed equally to this work
Innate immune cells that are initially drawn to a wound can subsequently be attracted away to nearby cancer cells and drive their proliferation.
Synopsis
This study reveals how innate immune cells, in particular neutrophils, that are initially drawn to a wound can subsequently be attracted away to nearby early‐ and late‐stage cancer cells and drive their proliferation. A video of this synopsis is available online at http://embopress.org/video_EMBOJ-2014-90147.
Both chronic and acute wounds exacerbate cancer growth.
Tissue damage in larval zebrafish, or cancer surgery in adults, draws in neutrophils and macrophages.
Neutrophils are recruited from wounds to nearby pre‐neoplastic cells and deliver trophic signals.
Neutrophil presence correlates with tumour cell proliferative index and indicates poor prognosis in ulcerated human melanoma.
The EMBO Journal (2015) 34: 2219–2236
- Received September 30, 2014.
- Revision received April 15, 2015.
- Accepted May 25, 2015.
- © 2015 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.
- Poised for action: USP18 restrains microglial activation in the white matter
Microglia are the resident macrophage population of the central nervous system (CNS) and are required for CNS development, homeostasis, and immune defense. Dysregulated microglial activity is involved in the pathogenesis of neuro‐degenerative conditions and is the dominant driver of neuro‐inflammatory diseases named “microgliopathies”. In this issue of The EMBO Journal, Goldmann et al reveal that white matter microglia in mice are actively maintained in a quiescent state via the ubiquitin‐specific protease (Usp) 18 (Goldmann et al, 2015). Removing this molecular blocker results in aggressive type I IFN‐mediated pathology, with features reminiscent of human microgliopathy. This study furthers our knowledge of the roles and regulation of microglial populations, adds insight into the processes underlying neuro‐inflammation, and broadens our consideration of immune regulation to include the concept of active restraint as a necessary component to avoid excessive inflammation.
See also: T Goldmann et al (June 2015)
Dedicated mechanisms actively maintain CNS macrophages in a quiescent state to avoid constitutive activation and immune pathology.
- © 2015 The Authors
- Cerebral nitric oxide represses choroid plexus NFκB‐dependent gateway activity for leukocyte trafficking
- 1Department of Neurobiology, Weizmann Institute of Science, Rehovot, Israel
- 2Department of Biological Services, Weizmann Institute of Science, Rehovot, Israel
- ↵*
Corresponding author. Tel: +972 89343638; E‐mail: kuti.baruch{at}weizmann.ac.il
Corresponding author. Tel: +972 89342467; E‐mail: michal.schwartz{at}weizmann.ac.il
↵† These authors contributed equally to the study
Neurodegenerative disorders are associated with excessive nitric oxide (NO) production. New findings show here that NO represses leukocyte trafficking to the CNS via inhibition of the NFκB/p65 signaling pathway.
Synopsis
The choroid plexus senses CSF‐borne danger/pro‐inflammatory signals, derived from the brain parenchyma, and maintains immune surveillance of the central nervous system. Under neurodegenerative conditions, cerebroventricular elevation of nitric oxide affects choroid plexus gateway dysfunction via repression of epithelial NFκB signaling pathway.
Intracerebroventricular administration of TNFα induces synchronized trafficking of leukocyte subsets to the cerebrospinal fluid via the choroid plexus.
Nitric oxide represses TNFα‐driven NFκB/p65 nuclear translocation in choroid plexus epithelial cells and inhibits the induction of leukocyte trafficking determinants expression.
Elevated nitric oxide levels at the choroid plexus of Alzheimer's disease transgenic mice are involved in repression of the NFκB signaling pathway.
The EMBO Journal (2015) 34: 1816–1828
- Received October 29, 2014.
- Revision received March 8, 2015.
- Accepted March 31, 2015.
- © 2015 The Authors
- USP18 lack in microglia causes destructive interferonopathy of the mouse brain
- Tobias Goldmann1,
- Nicolas Zeller1,
- Jenni Raasch1,
- Katrin Kierdorf1,
- Kathrin Frenzel1,
- Lars Ketscher1,
- Anja Basters1,
- Ori Staszewski1,
- Stefanie M Brendecke1,
- Alena Spiess1,
- Tuan Leng Tay1,
- Clemens Kreutz2,
- Jens Timmer2,3,
- Grazia MS Mancini4,
- Thomas Blank1,
- Günter Fritz1,
- Knut Biber5,6,
- Roland Lang7,
- Danielle Malo8,
- Doron Merkler9,
- Mathias Heikenwälder10,
- Klaus‐Peter Knobeloch1,† and
- Marco Prinz*,1,3,†
- 1Institute of Neuropathology, University of Freiburg, Freiburg, Germany
- 2Institute of Physics & Center for Systems Biology (ZBSA), University of Freiburg, Freiburg, Germany
- 3BIOSS Centre for Biological Signalling Studies, University of Freiburg, Freiburg, Germany
- 4Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands
- 5Department of Psychiatry, University of Freiburg, Freiburg, Germany
- 6Department of Neuroscience, University Medical Center Groningen, Groningen, The Netherlands
- 7Institute of Clinical Microbiology, Immunology and Hygiene, University Hospital Erlangen, Erlangen, Germany
- 8Department of Human Genetics, McGill University, Montreal, QC, Canada
- 9Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland
- 10Institute of Virology, Technische Universität München/Helmholtz‐Zentrum Munich, München, Germany
- ↵*Corresponding author. Tel: +49 761 270 51050; Fax: +49 761 270 50500; E‐mail: marco.prinz{at}uniklinik-freiburg.de
↵† These authors contributed equally to this work
The non‐catalytic anti‐inflammatory function of a deubiquitination enzyme plays a key role in preventing microglia activation and neuroinflammation in mouse brains.
Synopsis
This study identifies Usp18 as a new critical negative regulator of microglia activation and demonstrates a protective role of Usp18 for microglia function by regulating IFN signaling.
The protease USP18 is expressed in white matter microglia.
Loss of USP18 induces white matter microglia activation and leads to microgliopathy.
Microglia activation in the absence of USP18 is due to prolonged STAT1 phosphorylation.
Constitutive IFN type I signaling in microglia during steady state.
The Ifnar2 interaction domain rather then the protease function of USP19 controls microglia activation.
The EMBO Journal (2015) 34: 1612–1629
- Received December 12, 2014.
- Revision received March 3, 2015.
- Accepted March 17, 2015.
- © 2015 The Authors
- Tregs strip dendritic cells of CD70 to regulate Th1 differentiation
When the immune system encounters an antigen, the response can result in the mobilization of effector cells or in tolerance. The outcome is largely dependent on immunosuppressive CD4 T cells that express the transcription factor Foxp3 (Tregs). Yet, how Tregs control different immune effector cells remains elusive. In this issue of The EMBO Journal, Dhainaut et al report on a novel mechanism used by Tregs to prevent differentiation of naïve CD4 T cells to proinflammatory Th1CD4 (Th1) effectors.
See also: M Dhainaut et al (May 2015)
A recent study reveals a new mechanism by which regulatory T cells suppress excessive inflammatory responses.
- © 2015 The Authors
- Thymus‐derived regulatory T cells restrain pro‐inflammatory Th1 responses by downregulating CD70 on dendritic cells
- Maxime Dhainaut1,†,
- Caroline Coquerelle1,†,
- Sophie Uzureau1,
- Julie Denoeud1,
- Valérie Acolty1,
- Guillaume Oldenhove1,
- Adrien Galuppo1,2,
- Tim Sparwasser3,
- Kris Thielemans4,
- Etienne Pays1,
- Hideo Yagita5,
- Jannie Borst6 and
- Muriel Moser*,1
- 1Department of Molecular Biology, Université Libre de Bruxelles, Gosselies, Belgium
- 2Center for Microscopy and Molecular Imaging, Gosselies, Belgium
- 3Institute of Infection Immunology, Hannover, Germany
- 4Medical School, Vrije Universiteit Brussel, Brussels, Belgium
- 5Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan
- 6Division of Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands
- ↵*Corresponding author. Tel: +32 486303956; E‐mail: mmoser{at}ulb.ac.be
↵† These authors contributed equally to this work
Inhibition of the CD70/CD27 costimulatory pathway for Th1‐helper T‐cell priming exemplifies a new way for Treg‐cell suppression of excessive inflammatory responses.
Synopsis
Regulatory T cells (Tregs) control inflammatory responses by inhibiting the CD70‐dependent pathway of Th1 priming while sparing IL‐12 production. By decreasing CD70 cell surface expression on DCs, Tregs enhance the threshold of activation of Th1‐type responses, thereby restraining potentially harmful inflammatory responses.
Treg depletion results in enhanced Th1 priming in vivo.
Tregs downregulate CD70 protein levels at the plasma membrane of DCs by direct contact in a CD27‐dependent manner.
Intercellular transfer of CD27 receptor from T cells to CD70+ DCs leads to co‐internalization of both molecules, thereby limiting CD70 access for conventional T cells.
Conventional T cells upregulate CD27 upon activation, suggesting that a similar mechanism may be involved in the termination of immune responses.
The EMBO Journal (2015) 34: 1336–1348
- Received October 14, 2014.
- Revision received February 8, 2015.
- Accepted February 18, 2015.
- © 2015 The Authors
- An LXR–NCOA5 gene regulatory complex directs inflammatory crosstalk‐dependent repression of macrophage cholesterol efflux
- Mark A Gillespie1,
- Elizabeth S Gold2,
- Stephen A Ramsey3,
- Irina Podolsky2,
- Alan Aderem2 and
- Jeffrey A Ranish*,1
- 1Institute for Systems Biology, Seattle, WA, USA
- 2Seattle Biomedical Research Institute, Seattle, WA, USA
- 3Department of Biomedical Sciences, Oregon State University, Corvallis, OR, USA
- ↵*Corresponding author. Tel: +1 206 732 1357; Fax: +1 206 732 1299; E‐mail: jeff.ranish{at}systemsbiology.org
Inflammatory signaling impinges on LXR–NCOA5 dependent mechanisms controlling lipid transporter expression and macrophage cholesterol efflux.
Synopsis
NCOA5 is a key target of the crosstalk between pro‐inflammatory TLR3 signaling and the anti‐inflammatory LXR pathway. Here, NCOA5 functions as an LXR corepressor to attenuate expression of the lipid transporter Abca1, thereby providing a mechanism whereby inflammatory signaling leads to repression of macrophage cholesterol efflux.
Promoter enrichment‐quantitative mass spectrometry (PE‐QMS) maps the dynamic assembly of protein complexes at the Abca1 promoter.
PE‐QMS identifies the LXR ligand‐stimulated and LXR binding‐induced occupancy of NCOA5 at the Abca1 promoter.
In response to TLR3‐LXR signal crosstalk, NCOA5 is recruited to the Abca1 promoter, where it functions as an LXR corepressor.
NCOA5 inhibits Abca1 gene expression by disrupting RNA Polymerase II recruitment and function.
The EMBO Journal (2015) 34: 1244–1258
- Received August 15, 2014.
- Revision received February 11, 2015.
- Accepted February 13, 2015.
- © 2015 The Authors
- Regulatory T cell differentiation: cooperation saves the day
MicroRNA are important regulators of CD4 T cell differentiation, altering the balance between the immunogenic and tolerogenic pathways. Studies in mice with microRNA‐deficient T cells have revealed defects in differentiation into the regulatory T cell lineage; however, the individual microRNA responsible have remained elusive. A recent paper in The EMBO Journal uses a systematic screen to find a novel cooperative action between an inducible and a constitutive microRNA in aiding regulatory T cell induction.
See also: SC Warth et al (May 2015)
An inducible microRNA cooperates with a constitutive one to fine‐tune regulatory T cell induction.
- © 2015 The Authors
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