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Expression of the DNA-Binding Factor TOX Promotes the Encephalitogenic Potential of Microbe-Induced Autoreactive CD8+ T Cells.

  • Page N Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland.
  • Klimek B Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland.
  • De Roo M Department of Anesthesiology, Pharmacology and Intensive Care, Geneva University Hospital, Switzerland; Department of Basic Neuroscience, University of Geneva Medical School, Geneva, Switzerland.
  • Steinbach K Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland.
  • Soldati H Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland.
  • Lemeille S Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland.
  • Wagner I Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland.
  • Kreutzfeldt M Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland.
  • Di Liberto G Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland.
  • Vincenti I Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland.
  • Lingner T Microarray and Deep-Sequencing Core Facility, University Medical Center Göttingen, Göttingen, Germany.
  • Salinas G Microarray and Deep-Sequencing Core Facility, University Medical Center Göttingen, Göttingen, Germany.
  • Brück W Institute of Neuropathology, Georg-August University Göttingen, 37075 Göttingen, Germany.
  • Simons M Institute of Neuronal Cell Biology, Technical University Munich, Munich, Germany; German Center for Neurodegenerative Disease, 6250 Munich, Germany; Munich Cluster for Systems Neurology, 81377 Munich, Germany.
  • Murr R Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland; Institute for Genetics and Genomics in Geneva (iGE3), University of Geneva, Geneva, Switzerland.
  • Kaye J Research Division of Immunology, Departments of Biomedical Sciences and Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
  • Zehn D Division of Animal Physiology and Immunology, School of Life Sciences Weihenstephan, Technical University of Munich, Freising, Germany.
  • Pinschewer DD Division of Experimental Virology, Department of Biomedicine, Haus Petersplatz, University of Basel, Basel, Switzerland.
  • Merkler D Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland; Division of Clinical Pathology, Geneva University Hospital, Geneva, Switzerland. Electronic address: doron.merkler@unige.ch.
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  • 2018-05-17
Published in:
  • Immunity. - 2018
Listeria monocytogenes
T cell differentiation
autoimmunity
cytotoxic T cells
experimental autoimmune encephalomyelitis
lymphocytic choriomeningitis virus
multiple sclerosis
thymocyte selection-associated high-mobility group box factor
transcription factor
Adult
Aged
Animals
Autoimmunity
CD8-Positive T-Lymphocytes
Female
Homeodomain Proteins
Humans
Lymphocytic Choriomeningitis
Lymphocytic choriomeningitis virus
Male
Mice, Inbred C57BL
Mice, Knockout
Middle Aged
Signaling Lymphocytic Activation Molecule Family
T-Lymphocytes, Cytotoxic
English Infections are thought to trigger CD8+ cytotoxic T lymphocyte (CTL) responses during autoimmunity. However, the transcriptional programs governing the tissue-destructive potential of CTLs remain poorly defined. In a model of central nervous system (CNS) inflammation, we found that infection with lymphocytic choriomeningitis virus (LCMV), but not Listeria monocytogenes (Lm), drove autoimmunity. The DNA-binding factor TOX was induced in CTLs during LCMV infection and was essential for their encephalitogenic properties, and its expression was inhibited by interleukin-12 during Lm infection. TOX repressed the activity of several transcription factors (including Id2, TCF-1, and Notch) that are known to drive CTL differentiation. TOX also reduced immune checkpoint sensitivity by restraining the expression of the inhibitory checkpoint receptor CD244 on the surface of CTLs, leading to increased CTL-mediated damage in the CNS. Our results identify TOX as a transcriptional regulator of tissue-destructive CTLs in autoimmunity, offering a potential mechanistic link to microbial triggers.
Language
  • English
Open access status
bronze
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Persistent URL
https://sonar.ch/global/documents/46574
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