title: Tumor-necrosis factor impairs CD4(+) T cell-mediated immunological control in chronic viral infection.
abstract: Persistent viral infections are characterized by the simultaneous presence of chronic inflammation and T cell dysfunction. In prototypic models of chronicity--infection with human immunodeficiency virus (HIV) or lymphocytic choriomeningitis virus (LCMV)--we used transcriptome-based modeling to reveal that CD4(+) T cells were co-exposed not only to multiple inhibitory signals but also to tumor-necrosis factor (TNF). Blockade of TNF during chronic infection with LCMV abrogated the inhibitory gene-expression signature in CD4(+) T cells, including reduced expression of the inhibitory receptor PD-1, and reconstituted virus-specific immunity, which led to control of infection. Preventing signaling via the TNF receptor selectively in T cells sufficed to induce these effects. Targeted immunological interventions to disrupt the TNF-mediated link between chronic inflammation and T cell dysfunction might therefore lead to therapies to overcome persistent viral infection.
authors.affiliation: Life and Medical Sciences Bonn, Genomics &Immunoregulation, University of Bonn, Bonn, Germany.|Platform for Single Cell Genomics and Epigenomics at the German Center for Neurodegenerative Diseases and the University of Bonn, Bonn, Germany.
authors.forename: Marc
authors.identifier: http://orcid.org/0000-0001-9704-148X
authors.initials: M
authors.lastname: Beyer
authors.affiliation: Institute of Experimental Immunology, University Hospital Bonn, Bonn, Germany.
authors.forename: Zeinab
authors.initials: Z
authors.lastname: Abdullah
authors.affiliation: Department of Internal Medicine I, University Hospital Cologne, Cologne, Germany.
authors.forename: Jens M
authors.initials: JM
authors.lastname: Chemnitz
authors.affiliation: Department of Internal Medicine I, University Hospital Cologne, Cologne, Germany.
authors.forename: Daniela
authors.initials: D
authors.lastname: Maisel
authors.affiliation: Life and Medical Sciences Bonn, Genomics &Immunoregulation, University of Bonn, Bonn, Germany.
authors.forename: Jil
authors.initials: J
authors.lastname: Sander
authors.affiliation: Department of Internal Medicine I, University Hospital Cologne, Cologne, Germany.|German Center for Infection Research, partner site Bonn-Cologne, Cologne, Germany.
authors.forename: Clara
authors.initials: C
authors.lastname: Lehmann
authors.affiliation: Life and Medical Sciences Bonn, Genomics &Immunoregulation, University of Bonn, Bonn, Germany.|Department of Gastroenterology, Hepatology and Infectious Diseases, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany.
authors.forename: Yasser
authors.initials: Y
authors.lastname: Thabet
authors.affiliation: Department of Gastroenterology, Hepatology and Infectious Diseases, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany.
authors.forename: Prashant V
authors.initials: PV
authors.lastname: Shinde
authors.affiliation: Life and Medical Sciences Bonn, Genomics &Immunoregulation, University of Bonn, Bonn, Germany.
authors.forename: Lisa
authors.initials: L
authors.lastname: Schmidleithner
authors.affiliation: Life and Medical Sciences Bonn, Genomics &Immunoregulation, University of Bonn, Bonn, Germany.
authors.forename: Maren
authors.initials: M
authors.lastname: Köhne
authors.affiliation: Department of Internal Medicine I, University Hospital Bonn, Bonn, Germany.
authors.forename: Jonel
authors.initials: J
authors.lastname: Trebicka
authors.affiliation: Department of Internal Medicine I, University Hospital Bonn, Bonn, Germany.
authors.forename: Robert
authors.identifier: http://orcid.org/0000-0002-2195-3666
authors.initials: R
authors.lastname: Schierwagen
authors.affiliation: Life and Medical Sciences Bonn, Genomics &Immunoregulation, University of Bonn, Bonn, Germany.|Institute of Human Genetics, Department of Genomics, Life &Brain Center, University of Bonn, Bonn, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Hofmann
authors.affiliation: Life and Medical Sciences Bonn, Genomics &Immunoregulation, University of Bonn, Bonn, Germany.
authors.forename: Alexey
authors.initials: A
authors.lastname: Popov
authors.affiliation: Institute of Immunology, Faculty of Medicine, University of Duisburg-Essen, Essen, Germany.
authors.forename: Karl S
authors.initials: KS
authors.lastname: Lang
authors.affiliation: Institute of Microbiology, Swiss Federal Institute of Technology Zürich, Zürich, Switzerland.
authors.forename: Annette
authors.initials: A
authors.lastname: Oxenius
authors.affiliation: Institute of Laboratory Animal Science, University of Zürich, Schlieren, Switzerland.
authors.forename: Thorsten
authors.identifier: http://orcid.org/0000-0002-2236-9074
authors.initials: T
authors.lastname: Buch
authors.affiliation: Institute of Experimental Immunology, University Hospital Bonn, Bonn, Germany.
authors.forename: Christian
authors.identifier: http://orcid.org/0000-0002-6620-2401
authors.initials: C
authors.lastname: Kurts
authors.affiliation: Institute of Virology, Technische Universität/Helmholtz Zentrum München, München, Germany.|Division of Chronic Inflammation and Cancer, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Mathias
authors.initials: M
authors.lastname: Heikenwalder
authors.affiliation: Department of Internal Medicine I, University Hospital Cologne, Cologne, Germany.|German Center for Infection Research, partner site Bonn-Cologne, Cologne, Germany.
authors.forename: Gerd
authors.initials: G
authors.lastname: Fätkenheuer
authors.affiliation: Department of Gastroenterology, Hepatology and Infectious Diseases, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany.|Department of Molecular Medicine II, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany.
authors.forename: Philipp A
authors.initials: PA
authors.lastname: Lang
authors.affiliation: Department of Internal Medicine I, University Hospital Cologne, Cologne, Germany.|German Center for Infection Research, partner site Bonn-Cologne, Cologne, Germany.|Institute for Medical Microbiology, Immunology and Hygiene, University of Cologne, Cologne, Germany.
authors.forename: Pia
authors.initials: P
authors.lastname: Hartmann
authors.affiliation: Institute of Experimental Immunology, University Hospital Bonn, Bonn, Germany.|Institute of Molecular Immunology, Klinikum rechts der Isar, Technische Universität München, München, Germany.
authors.forename: Percy A
authors.identifier: http://orcid.org/0000-0003-2983-0414
authors.initials: PA
authors.lastname: Knolle
authors.affiliation: Life and Medical Sciences Bonn, Genomics &Immunoregulation, University of Bonn, Bonn, Germany.|Platform for Single Cell Genomics and Epigenomics at the German Center for Neurodegenerative Diseases and the University of Bonn, Bonn, Germany.
authors.forename: Joachim L
authors.initials: JL
authors.lastname: Schultze
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D005434:Flow Cytometry; D057809:HEK293 Cells; D006678:HIV / Q000276:immunology* / Q000502:physiology; D015658:HIV Infections / Q000235:genetics / Q000276:immunology* / Q000821:virology; D054884:Host-Pathogen Interactions / Q000276:immunology; D006801:Humans; D015151:Immunoblotting; D008216:Lymphocytic Choriomeningitis / Q000235:genetics / Q000276:immunology* / Q000821:virology; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology* / Q000502:physiology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D061026:Programmed Cell Death 1 Receptor / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D059467:Transcriptome / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology* / Q000378:metabolism / Q000494:pharmacology; D055815:Young Adult
chemical_list: D061026:Programmed Cell Death 1 Receptor; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha