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  • 1
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    A cryptic sensor for HIV-1 activates antiviral innate immunity in dendritic cells (2010)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2010-09-11
    Description: Dendritic cells serve a key function in host defence, linking innate detection of microbes to activation of pathogen-specific adaptive immune responses. Whether there is cell-intrinsic recognition of human immunodeficiency virus (HIV) by host innate pattern-recognition receptors and subsequent coupling to antiviral T-cell responses is not yet known. Dendritic cells are largely resistant to infection with HIV-1, but facilitate infection of co-cultured T-helper cells through a process of trans-enhancement. Here we show that, when dendritic cell resistance to infection is circumvented, HIV-1 induces dendritic cell maturation, an antiviral type I interferon response and activation of T cells. This innate response is dependent on the interaction of newly synthesized HIV-1 capsid with cellular cyclophilin A (CYPA) and the subsequent activation of the transcription factor IRF3. Because the peptidylprolyl isomerase CYPA also interacts with HIV-1 capsid to promote infectivity, our results indicate that capsid conformation has evolved under opposing selective pressures for infectivity versus furtiveness. Thus, a cell-intrinsic sensor for HIV-1 exists in dendritic cells and mediates an antiviral immune response, but it is not typically engaged owing to the absence of dendritic cell infection. The virulence of HIV-1 may be related to evasion of this response, the manipulation of which may be necessary to generate an effective HIV-1 vaccine.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3051279/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3051279/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Manel, Nicolas -- Hogstad, Brandon -- Wang, Yaming -- Levy, David E -- Unutmaz, Derya -- Littman, Dan R -- AI28900/AI/NIAID NIH HHS/ -- AI33856/AI/NIAID NIH HHS/ -- R01 AI033856/AI/NIAID NIH HHS/ -- R01 AI033856-16/AI/NIAID NIH HHS/ -- R01AI065303/AI/NIAID NIH HHS/ -- R21 AI084633/AI/NIAID NIH HHS/ -- U54-AI057158/AI/NIAID NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2010 Sep 9;467(7312):214-7. doi: 10.1038/nature09337.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Molecular Pathogenesis Program, The Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine, New York, New York 10016, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20829794" target="_blank"〉PubMed〈/a〉
    Keywords: Capsid Proteins/immunology ; Cell Line ; Cyclophilin A/immunology ; Dendritic Cells/cytology/*immunology/metabolism/*virology ; HIV Infections/*immunology/virology ; HIV-1/*immunology/physiology ; Humans ; *Immunity, Innate ; Interferon Regulatory Factor-3/genetics/metabolism ; Lymphocyte Activation ; Monocytes/cytology ; T-Lymphocytes/immunology
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 2
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    Digoxin and its derivatives suppress TH17 cell differentiation by antagonizing RORgammat activity (2011)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2011-03-29
    Description: CD4(+) T helper lymphocytes that express interleukin-17 (T(H)17 cells) have critical roles in mouse models of autoimmunity, and there is mounting evidence that they also influence inflammatory processes in humans. Genome-wide association studies in humans have linked genes involved in T(H)17 cell differentiation and function with susceptibility to Crohn's disease, rheumatoid arthritis and psoriasis. Thus, the pathway towards differentiation of T(H)17 cells and, perhaps, of related innate lymphoid cells with similar effector functions, is an attractive target for therapeutic applications. Mouse and human T(H)17 cells are distinguished by expression of the retinoic acid receptor-related orphan nuclear receptor RORgammat, which is required for induction of IL-17 transcription and for the manifestation of T(H)17-dependent autoimmune disease in mice. By performing a chemical screen with an insect cell-based reporter system, we identified the cardiac glycoside digoxin as a specific inhibitor of RORgammat transcriptional activity. Digoxin inhibited murine T(H)17 cell differentiation without affecting differentiation of other T cell lineages and was effective in delaying the onset and reducing the severity of autoimmune disease in mice. At high concentrations, digoxin is toxic for human cells, but non-toxic synthetic derivatives 20,22-dihydrodigoxin-21,23-diol and digoxin-21-salicylidene specifically inhibited induction of IL-17 in human CD4(+) T cells. Using these small-molecule compounds, we demonstrate that RORgammat is important for the maintenance of IL-17 expression in mouse and human effector T cells. These data indicate that derivatives of digoxin can be used as chemical templates for the development of RORgammat-targeted therapeutic agents that attenuate inflammatory lymphocyte function and autoimmune disease.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3172133/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3172133/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Huh, Jun R -- Leung, Monica W L -- Huang, Pengxiang -- Ryan, Daniel A -- Krout, Michael R -- Malapaka, Raghu R V -- Chow, Jonathan -- Manel, Nicolas -- Ciofani, Maria -- Kim, Sangwon V -- Cuesta, Adolfo -- Santori, Fabio R -- Lafaille, Juan J -- Xu, H Eric -- Gin, David Y -- Rastinejad, Fraydoon -- Littman, Dan R -- 2R01GM55217/GM/NIGMS NIH HHS/ -- F32GM0860552/GM/NIGMS NIH HHS/ -- R01 AI080885/AI/NIAID NIH HHS/ -- R01AI080885/AI/NIAID NIH HHS/ -- R01GM058833/GM/NIGMS NIH HHS/ -- R01GM067659/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2011 Apr 28;472(7344):486-90. doi: 10.1038/nature09978. Epub 2011 Mar 27.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Molecular Pathogenesis Program, The Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine, New York, New York 10016, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21441909" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Autoimmune Diseases/drug therapy/immunology/pathology ; Autoimmunity/drug effects/immunology ; Cell Differentiation/*drug effects ; Cell Line ; Digoxin/*analogs & derivatives/chemistry/metabolism/*pharmacology/therapeutic use ; Drosophila/cytology ; Humans ; Interleukin-17/biosynthesis/immunology ; Mice ; Nuclear Receptor Subfamily 1, Group F, Member 3/*antagonists & ; inhibitors/metabolism ; Th17 Cells/*cytology/*drug effects/immunology ; Transcription, Genetic/drug effects/genetics
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 3
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    Transmission of innate immune signaling by packaging of cGAMP in viral particles (2015)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2015-08-01
    Description: Infected cells detect viruses through a variety of receptors that initiate cell-intrinsic innate defense responses. Cyclic guanosine monophosphate (GMP)-adenosine monophosphate (AMP) synthase (cGAS) is a cytosolic sensor for many DNA viruses and HIV-1. In response to cytosolic viral DNA, cGAS synthesizes the second messenger 2'3'-cyclic GMP-AMP (cGAMP), which activates antiviral signaling pathways. We show that in cells producing virus, cGAS-synthesized cGAMP can be packaged in viral particles and extracellular vesicles. Viral particles efficiently delivered cGAMP to target cells. cGAMP transfer by viral particles to dendritic cells activated innate immunity and antiviral defenses. Finally, we show that cell-free murine cytomegalovirus and Modified Vaccinia Ankara virus contained cGAMP. Thus, transfer of cGAMP by viruses may represent a defense mechanism to propagate immune responses to uninfected target cells.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Gentili, Matteo -- Kowal, Joanna -- Tkach, Mercedes -- Satoh, Takeshi -- Lahaye, Xavier -- Conrad, Cecile -- Boyron, Marilyn -- Lombard, Berangere -- Durand, Sylvere -- Kroemer, Guido -- Loew, Damarys -- Dalod, Marc -- Thery, Clotilde -- Manel, Nicolas -- New York, N.Y. -- Science. 2015 Sep 11;349(6253):1232-6. doi: 10.1126/science.aab3628. Epub 2015 Jul 30.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉INSERM U932, Immunity and Cancer Unit, Institut Curie, Paris, France. ; Centre d'Immunologie de Marseille-Luminy, Aix Marseille Universite UM2, INSERM U1104, CNRS UMR7280, 13288 Marseille, France. ; Laboratoire de Spectrometrie de Masse Proteomique, Institut Curie, Paris, France. ; Labex Dendritic Cell Biology (DCBIOL), Paris, France. ; Metabolomics and Cell Biology Platforms, Gustave Roussy Comprehensive Cancer Institute, 94805 Villejuif, France. ; INSERM U932, Immunity and Cancer Unit, Institut Curie, Paris, France. Labex Dendritic Cell Biology (DCBIOL), Paris, France. ; INSERM U932, Immunity and Cancer Unit, Institut Curie, Paris, France. Labex Dendritic Cell Biology (DCBIOL), Paris, France. Labex Vaccine Research Institute (VRI), Paris, France. nicolas.manel@curie.fr.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26229115" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cercopithecus aethiops ; Cytosol/immunology/metabolism/virology ; Dendritic Cells/*immunology/virology ; Genetic Vectors/genetics/metabolism ; HIV Infections/immunology ; HIV-1/genetics/metabolism ; HeLa Cells ; Herpesviridae Infections/*immunology ; Humans ; Immunity, Innate/genetics/*immunology ; Mice ; Mice, Inbred C57BL ; Muromegalovirus/genetics/*metabolism ; Nucleotides, Cyclic/*metabolism ; *Second Messenger Systems ; Vaccinia/*immunology ; Vaccinia virus/genetics/*metabolism ; Vero Cells ; Virion/genetics/*metabolism ; Virus Assembly
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
    Published by American Association for the Advancement of Science (AAAS)
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  • 4
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    ESCRT III repairs nuclear envelope ruptures during cell migration to limit DNA damage and cell death (2016)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2016-03-26
    Description: In eukaryotic cells, the nuclear envelope separates the genomic DNA from the cytoplasmic space and regulates protein trafficking between the two compartments. This barrier is only transiently dissolved during mitosis. Here, we found that it also opened at high frequency in migrating mammalian cells during interphase, which allowed nuclear proteins to leak out and cytoplasmic proteins to leak in. This transient opening was caused by nuclear deformation and was rapidly repaired in an ESCRT (endosomal sorting complexes required for transport)-dependent manner. DNA double-strand breaks coincided with nuclear envelope opening events. As a consequence, survival of cells migrating through confining environments depended on efficient nuclear envelope and DNA repair machineries. Nuclear envelope opening in migrating leukocytes could have potentially important consequences for normal and pathological immune responses.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Raab, M -- Gentili, M -- de Belly, H -- Thiam, H R -- Vargas, P -- Jimenez, A J -- Lautenschlaeger, F -- Voituriez, Raphael -- Lennon-Dumenil, A M -- Manel, N -- Piel, M -- New York, N.Y. -- Science. 2016 Apr 15;352(6283):359-62. doi: 10.1126/science.aad7611. Epub 2016 Mar 24.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institut Curie, PSL Research University, CNRS, UMR 144, F-75005 Paris, France. Institut Pierre-Gilles de Gennes, PSL Research University, F-75005 Paris, France. ; Institut Curie, PSL Research University, INSERM, U 932, F-75005 Paris, France. ; Institut Curie, PSL Research University, CNRS, UMR 144, F-75005 Paris, France. ; Laboratoire de Physique Theorique de la Matiere Condensee, CNRS UMR 7600, Universite Pierre et Marie Curie, Paris, France. Laboratoire Jean Perrin, CNRS UMR 8237, Universite Pierre et Marie Curie, Paris, France. ; Institut Curie, PSL Research University, CNRS, UMR 144, F-75005 Paris, France. Institut Pierre-Gilles de Gennes, PSL Research University, F-75005 Paris, France. matthieu.piel@curie.fr.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27013426" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Death ; *Cell Movement ; Cytoplasm/metabolism ; *DNA Breaks, Double-Stranded ; DNA Repair ; Endosomal Sorting Complexes Required for Transport/genetics/*metabolism ; HeLa Cells ; Humans ; Immunity/genetics ; Interphase ; Leukocytes/immunology/ultrastructure ; Mice ; Nuclear Envelope/*ultrastructure ; Nuclear Proteins/metabolism
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 5
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    Glucose transporter 1 expression identifies a population of cycling CD4+CD8+ human thymocytes with high CXCR4-induced chemotaxis (2005)
    National Academy of Sciences
    Details
    Publication Date: 2005-08-26
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
    Published by National Academy of Sciences
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  • 6
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    Preferential retroviral-mediated transduction of EBV- and CMV-specific T cells after polyclonal T-cell activation (2004)
    Springer Nature
    Details
    Publication Date: 2004-04-22
    Print ISSN: 0969-7128
    Electronic ISSN: 1476-5462
    Topics: Biology , Medicine
    Published by Springer Nature
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  • 7
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    Role of microbiota and transcription factors in control of Th17 cell differentiation (2009)
    Elsevier
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    Publication Date: 2009-10-01
    Print ISSN: 1043-4666
    Electronic ISSN: 1096-0023
    Topics: Biology , Medicine
    Published by Elsevier
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  • 8
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    The nucleus acts as a ruler tailoring cell responses to spatial constraints (2020)
    American Association for the Advancement of Science
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    Publication Date: 2020-10-15
    Description: The microscopic environment inside a metazoan organism is highly crowded. Whether individual cells can tailor their behavior to the limited space remains unclear. In this study, we found that cells measure the degree of spatial confinement by using their largest and stiffest organelle, the nucleus. Cell confinement below a resting nucleus size deforms the nucleus, which expands and stretches its envelope. This activates signaling to the actomyosin cortex via nuclear envelope stretch-sensitive proteins, up-regulating cell contractility. We established that the tailored contractile response constitutes a nuclear ruler–based signaling pathway involved in migratory cell behaviors. Cells rely on the nuclear ruler to modulate the motive force that enables their passage through restrictive pores in complex three-dimensional environments, a process relevant to cancer cell invasion, immune responses, and embryonic development.
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
    Published by American Association for the Advancement of Science
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