Immunology
- 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
- Induced miR‐99a expression represses Mtor cooperatively with miR‐150 to promote regulatory T‐cell differentiation
- Sebastian C Warth1,
- Kai P Hoefig1,
- Anian Hiekel1,5,
- Sonja Schallenberg2,
- Ksenija Jovanovic3,6,
- Ludger Klein3,
- Karsten Kretschmer2,
- K Mark Ansel4 and
- Vigo Heissmeyer*,1,3
- 1Helmholtz Zentrum München, Research Unit Molecular Immune Regulation, Institute of Molecular Immunology, Munich, Germany
- 2Molecular and Cellular Immunology/Immune Regulation, DFG‐Center for Regenerative Therapies Dresden (CRTD), Technische Universität Dresden, Dresden, Germany
- 3Institute for Immunology, University of Munich, Munich, Germany
- 4Department of Microbiology and Immunology, University of California San Francisco, San Francisco, CA, USA
- 5Gene Center, Department of Chemistry and Biochemistry, University of Munich, Munich, Germany
- 6Department of General, Visceral, Transplantation and Thoracic Surgery, University Hospital of Munich, Munich, Germany
- ↵*Corresponding author. Tel: +49 89 2180 75629; E‐mail: vigo.heissmeyer{at}med.uni-muenchen.de
miRNAs identified in an overexpression screen reveal the importance of coordinated suppression of mTOR expression for promoting Treg induction.
Synopsis
miRNAs identified in an overexpression screen reveal the importance of coordinated suppression of mTOR expression for promoting Treg induction.
Many microRNAs have a positive while others a negative effect on naive T‐cell differentiation into Tregs.
miR‐99a and miR‐150 promote Treg differentiation.
The highly expressed miR‐150 contributes at physiological levels while the lower expressed miR‐99a is inducible.
The neighboring target sites of miR‐150 and miR‐99a in the 3′ UTR of the Mtor mRNA show the importance of cooperative miRNA‐mediated repression.
The EMBO Journal (2015) 34: 1195–1213
- Received July 22, 2014.
- Revision received December 19, 2014.
- Accepted January 21, 2015.
- © 2015 The Authors
- The BAFFling function of Syk in B‐cell homeostasis
The TNF receptor family member BAFFR is essential for providing mature B cells with pro‐survival signals and has recently been claimed to transduce these, though not exclusively, via a Syk‐dependent signaling hub that feeds into ERK/AKT activation. In this issue of The EMBO Journal, Hobeika et al (2015) describe a synergistic pro‐survival scenario involving BAFFR and CD19, which remains functional under Syk null conditions and is able to maintain mature B‐cell survival. The authors hence propose a BAFFR‐/CD19‐driven mechanism to act in parallel with homeostatic NF‐κB/AKT activation in non‐stimulated B cells.
See also: E Hobeika et al (April 2015)
The BAFFR/CD19 pathway promotes B‐cell survival in parallel with canonical Syk‐dependent homeostatic NF‐κB/AKT activation.
- © 2015 The Authors
- In‐TOX‐icating neurogenesis
- 1Physiological Genomics, Institute of Physiology, Ludwig‐Maximilians University Munich, Munich, Germany
- 2Laboratory “Adult Neurogenesis and Cellular Reprogramming”, Institute of Physiological Chemistry, University Medical Center Johannes Gutenberg University Mainz, Mainz, Germany
- 3Focus Program Translational Neuroscience, Johannes Gutenberg University Mainz, Mainz, Germany
Early development of the mammalian cerebral cortex proceeds via a sequence of proliferative and differentiative steps from neural stem cells toward neurons and glia. However, how these steps are molecularly orchestrated is still only partially understood. In this issue of The EMBO Journal, Artegiani and colleagues implicate Tox, a HMG‐box transcription factor previously known only for its role in lymphocyte development, in early cortical development.
See also: B Artegiani et al (April 2015)
The HMG‐box transcription factor Tox regulates neural stem cell expansion, fate decisions and neuronal differentiation during early cortical development.
- © 2015 The Authors
- Space exploration by dendritic cells requires maintenance of myosin II activity by IP3 receptor 1
- Paola Solanes1,
- Mélina L Heuzé1,†,
- Mathieu Maurin1,†,
- Marine Bretou1,
- Franziska Lautenschlaeger2,
- Paolo Maiuri2,
- Emmanuel Terriac2,
- Maria‐Isabel Thoulouze3,
- Pierre Launay4,
- Matthieu Piel2,
- Pablo Vargas*,1 and
- Ana‐Maria Lennon‐Duménil*,1
- 1Inserm‐U932 Institut Curie, Paris, France
- 2CNRS‐UMR144 Institut Curie, Paris, France
- 3Unité de Virologie Structurale, CNRS‐UMR3469 Institut Pasteur, Paris, France
- 4Faculté de Médecine X. Bichat, Inserm‐U1149, Paris, France
- ↵*
Corresponding author. Tel: +33 1 56 24 63 83; Fax: +33 1 56 24 63 19; E‐mail: pablo.vargas{at}curie.fr
Corresponding author. Tel: +33 1 56 24 64 27; Fax: +33 1 56 24 64 38; E‐mail: amlennon{at}curie.fr
↵† Equal contribution by alphabetical order
The IP3 receptor IP3R1 controls the ability of immature dendritic cells to explore their environment by regulating calcium release from the endoplasmic reticulum and by reinforcing the activity of the myosin light chain (MLC) kinase.
Synopsis
The IP3 receptor IP3R1 controls the ability of immature dendritic cells to explore their environment by regulating calcium release from the endoplasmic reticulum and by reinforcing the activity of the myosin light chain (MLC) kinase.
Immature dendritic cells migrating in confinement exhibit peaks of calcium release during phases of fast locomotion.
The migration of immature dendritic cells does not require extracellular calcium.
Silencing of IP3R isoforms reduces the migration speed of immature dendritic cells.
IP3R1 silencing specifically compromises the migration persistence of immature dendritic cells in 1‐, 2‐, and 3‐dimensional‐confined environments.
By activating the MLC kinase, IP3R1 maintains the phosphorylation levels of MLC and the back/front polarization of myosin II in migrating immature dendritic cells.
The EMBO Journal (2015) 34: 798–810
- Received May 22, 2014.
- Revision received December 16, 2014.
- Accepted December 18, 2014.
- © 2015 Institut Curie/Inserm. Published under the terms of the CC BY NC ND 4.0 license
This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs 4.0 License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
- CD19 and BAFF‐R can signal to promote B‐cell survival in the absence of Syk
- Elias Hobeika*,1,2,†,
- Ella Levit‐Zerdoun1,†,
- Vasiliki Anastasopoulou3,
- Roland Pohlmeyer1,
- Simon Altmeier4,
- Ameera Alsadeq5,
- Marc‐Werner Dobenecker6,
- Roberta Pelanda7 and
- Michael Reth*,1,2,8
- 1Max‐Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany
- 2Department of Molecular Immunology, BioIII, Faculty of Biology, Albert‐Ludwigs‐Universität Freiburg, Freiburg, Germany
- 3Institute of Immunology, Charité Campus Buch, Berlin, Germany
- 4Institute of Mircobiology, Swiss Federal Institute of Technology, ETH Zurich, Zurich, Switzerland
- 5Department of General Pediatrics, University Medical Center Schleswig‐Holstein, Kiel, Germany
- 6Laboratory of Immune Cell Epigenetics and Signaling, The Rockefeller University, New York, NY, USA
- 7Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO, USA
- 8BIOSS, Centre For Biological Signaling Studies, University of Freiburg, Freiburg, Germany
- ↵*
Corresponding author. Tel: +49 761 5108422; Fax: +49 761 5108423; E‐mail: hobeika{at}ie-freiburg.mpg.de
Corresponding author. Tel: +49 761 5108420; Fax: +49 761 5108423; E‐mail: michael.reth{at}bioss.uni-freiburg.de
-
↵† These authors contributed equally to this work
Syk‐deficient B cells require BAFF receptor and CD19/PI3K signaling for their long‐term survival and maintenance.
Synopsis
Survival of mature murine B cells primarily depends of signals from the BCR and BAFF‐R. Downstream of the BCR, the kinase Syk plays a pivotal role in the activation of various cell survival pathways including the PI3K pathway. Our in vivo experiments show that a considerable fraction of mature Syk‐negative B cells can survive however they require BAFF receptor and CD19/PI3K signaling for their long‐term maintenance.
A fraction of mature B cells (˜25%) can be maintained in the absence of the kinase Syk over a prolonged time frame in spite of defective BCR signaling and the inability to activate the mTORC1 pathway in response to BCR ligation.
This maintenance is dependent on signals from the BAFF receptor since blocking of BAFF—BAFF‐R interaction results in decreased numbers of Syk‐deficient B cells.
Furthermore, the expression of the BCR coreceptor CD19, which upon phosphorylation by Syk promotes PI3K activation, is required for the survival of Syk‐deficient B cells.
The viability of CD19; Syk double‐deficient B cells is restored by the conditional ablation of FoxO1, the latter mimicking hyperactive PI3K activation.
The EMBO Journal (2015) 34: 925–939
- Received August 6, 2014.
- Revision received December 23, 2014.
- Accepted January 2, 2015.
- © 2015 The Authors
- Commensal microbiota influence systemic autoimmune responses
- Jens T Van Praet1,†,
- Erin Donovan1,†,
- Inge Vanassche1,
- Michael B Drennan1,
- Fien Windels1,
- Amélie Dendooven2,
- Liesbeth Allais3,
- Claude A Cuvelier3,
- Fons van de Loo4,
- Paula S Norris5,
- Andrey A Kruglov6,7,
- Sergei A Nedospasov8,
- Sylvie Rabot9,10,
- Raul Tito11,
- Jeroen Raes11,
- Valerie Gaboriau‐Routhiau9,12,
- Nadine Cerf‐Bensussan12,
- Tom Van de Wiele13,
- Gérard Eberl14,
- Carl F Ware5 and
- Dirk Elewaut*,1,15
- 1Laboratory for Molecular Immunology and Inflammation, Department of Rheumatology, Ghent University Hospital, Ghent, Belgium
- 2Department of Pathology, University Medical Center, Utrecht, the Netherlands
- 3Department of Pathology, Ghent University Hospital, Ghent, Belgium
- 4Department of Rheumatology, Radboud University Medical Center, Nijmegen, the Netherlands
- 5Infectious and Inflammatory Disease Center, Sanford‐Burnham Medical Research Institute, La Jolla, CA, USA
- 6German Rheumatism Research Center (DRFZ), A Leibniz Institute, Berlin, Germany
- 7Belozersky Institute of Physico‐Chemical Biology and Biological Faculty, Lomonosov Moscow State University, Moscow, Russia
- 8Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, and Lomonosov Moscow State University, Moscow, Russia
- 9INRA, UMR1319 Micalis, Jouy‐en‐Josas, France
- 10AgroParisTech Micalis, Jouy‐en‐Josas, France
- 11Bioinformatics and (eco‐)systems Biology Laboratory, Department of Microbiology and Immunology, Rega Institute VIB Center for the Biology of Disease, KU Leuven, Belgium
- 12INSERM UMR1163, Laboratory of Intestinal Immunity, Université Paris Descartes‐Sorbonne Paris Cité and Institut Imagine, Paris, France
- 13Laboratory of Microbial Ecology and Technology, Ghent University, Ghent, Belgium
- 14Lymphoid Tissue Development Group, Institut Pasteur, Paris, France
- 15VIB Inflammation Research Center Ghent University, Ghent, Belgium
- ↵*Corresponding author. Tel: +329 332 2240; E‐mail: Dirk.Elewaut{at}ugent.be
↵† These authors contributed equally to this work
Neonatal colonization of the intestine by segmented filamentous bacteria affects systemic autoimmune responses against nuclear antigens in adult life.
Synopsis
Antinuclear antibodies (ANA) are features of generalized autoimmune diseases. Here, we show that induction of ANA spontaneously occurs in mice lacking gut‐associated lymphoid tissues. This was caused by colonization of the intestine by segmented filamentous bacteria, which are potent inducers of Th17 responses. Microbiota and IL‐17R‐dependent mechanism of ANA induction embark in the neonatal phase of life, leading to systemic autoimmunity in adult.
ANA induction may occur in the absence of all secondary lymphoid organs, particularly gut‐associated lymphoid tissues
Spontaneous occurrence of ANA in the absence of lymphotoxin is RORγt and IL‐17R dependent.
Neonatal colonization of the intestine by segmented filamentous bacteria in the absence of gut‐associated lymphoid tissues predisposes for ANA induction in adult life
The EMBO Journal (2015) 34: 466–474
- Received September 3, 2014.
- Revision received November 12, 2014.
- Accepted December 1, 2014.
- © 2015 The Authors
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