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TOX reinforces the phenotype and longevity of exhausted T cells in chronic viral infection.
Journal article

TOX reinforces the phenotype and longevity of exhausted T cells in chronic viral infection.

  • Alfei F Division of Animal Physiology and Immunology, School of Life Sciences Weihenstephan, Technical University of Munich, Freising, Germany.
  • Kanev K Division of Animal Physiology and Immunology, School of Life Sciences Weihenstephan, Technical University of Munich, Freising, Germany.
  • Hofmann M Universitätsklinikum Freiburg, Klinik für Innere Medizin II, University of Freiburg, Freiburg, Germany.
  • Wu M Division of Animal Physiology and Immunology, School of Life Sciences Weihenstephan, Technical University of Munich, Freising, Germany.
  • Ghoneim HE Department of Immunology, St Jude Children's Research Hospital, Memphis, TN, USA.
  • Roelli P Division of Animal Physiology and Immunology, School of Life Sciences Weihenstephan, Technical University of Munich, Freising, Germany.
  • Utzschneider DT Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, Victoria, Australia.
  • von Hoesslin M Division of Animal Physiology and Immunology, School of Life Sciences Weihenstephan, Technical University of Munich, Freising, Germany.
  • Cullen JG Division of Animal Physiology and Immunology, School of Life Sciences Weihenstephan, Technical University of Munich, Freising, Germany.
  • Fan Y The Department of Computational Biology, St Jude Children's Research Hospital, Memphis, TN, USA.
  • Eisenberg V The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat Gan, Israel.
  • Wohlleber D Institute of Molecular Immunology and Experimental Oncology, University Hospital Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.
  • Steiger K Comparative Experimental Pathology, Institute of Pathology, Technical University of Munich, Munich, Germany.
  • Merkler D Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland.
  • Delorenzi M Swiss Institute of Bioinformatics (SIB), University of Lausanne, Lausanne, Switzerland.
  • Knolle PA Institute of Molecular Immunology and Experimental Oncology, University Hospital Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.
  • Cohen CJ The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat Gan, Israel.
  • Thimme R Universitätsklinikum Freiburg, Klinik für Innere Medizin II, University of Freiburg, Freiburg, Germany. robert.thimme@uniklinik-freiburg.de.
  • Youngblood B Department of Immunology, St Jude Children's Research Hospital, Memphis, TN, USA. Benjamin.youngblood@stjude.org.
  • Zehn D Division of Animal Physiology and Immunology, School of Life Sciences Weihenstephan, Technical University of Munich, Freising, Germany. dietmar.zehn@tum.de.
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  • 2019-06-18
Published in:
  • Nature. - 2019
Animals
CD8-Positive T-Lymphocytes
Cell Proliferation
Chronic Disease
Cytokines
Epigenesis, Genetic
Female
Gene Expression Regulation
Hepacivirus
Hepatitis C, Chronic
Hepatocyte Nuclear Factor 1-alpha
High Mobility Group Proteins
Homeodomain Proteins
Humans
Immunologic Memory
Lymphocytic Choriomeningitis
Lymphocytic choriomeningitis virus
Male
Mice
Phenotype
Thymocytes
Transcription, Genetic
English Cytotoxic T cells are essential mediators of protective immunity to viral infection and malignant tumours and are a key target of immunotherapy approaches. However, prolonged exposure to cognate antigens often attenuates the effector capacity of T cells and limits their therapeutic potential1-4. This process, known as T cell exhaustion or dysfunction1, is manifested by epigenetically enforced changes in gene regulation that reduce the expression of cytokines and effector molecules and upregulate the expression of inhibitory receptors such as programmed cell-death 1 (PD-1)5-8. The underlying molecular mechanisms that induce and stabilize the phenotypic and functional features of exhausted T cells remain poorly understood9-12. Here we report that the development and maintenance of populations of exhausted T cells in mice requires the thymocyte selection-associated high mobility group box (TOX) protein13-15. TOX is induced by high antigen stimulation of the T cell receptor and correlates with the presence of an exhausted phenotype during chronic infections with lymphocytic choriomeningitis virus in mice and hepatitis C virus in humans. Removal of its DNA-binding domain reduces the expression of PD-1 at the mRNA and protein level, augments the production of cytokines and results in a more polyfunctional T cell phenotype. T cells with this deletion initially mediate increased effector function and cause more severe immunopathology, but ultimately undergo a massive decline in their quantity, notably among the subset of TCF-1+ self-renewing T cells. Altogether, we show that TOX is a critical factor for the normal progression of T cell dysfunction and the maintenance of exhausted T cells during chronic infection, and provide a link between the suppression of effector function intrinsic to CD8 T cells and protection against immunopathology.
Language
  • English
Open access status
closed
Identifiers
Persistent URL
https://folia.unifr.ch/global/documents/70141
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