Tumor-necrosis factor impairs CD4(+) T cell-mediated immunological control in chronic viral infection

Marc Beyer; Zeinab Abdullah; Jens M Chemnitz; Daniela Maisel; Jil Sander; Clara Lehmann; Yasser Thabet; Prashant V Shinde; Lisa Schmidleithner; Maren Köhne; Jonel Trebicka; Robert Schierwagen; Andrea Hofmann; Alexey Popov; Karl S Lang; Annette Oxenius; Thorsten Buch; Christian Kurts; Mathias Heikenwalder; Gerd Fätkenheuer; Philipp A Lang; Pia Hartmann; Percy A Knolle; Joachim L Schultze

doi:10.1038/ni.3399

Tumor-necrosis factor impairs CD4(+) T cell-mediated immunological control in chronic viral infection

Nat Immunol. 2016 May;17(5):593-603. doi: 10.1038/ni.3399. Epub 2016 Mar 7.

Authors

Marc Beyer^{1

2}, Zeinab Abdullah³, Jens M Chemnitz⁴, Daniela Maisel⁴, Jil Sander¹, Clara Lehmann^{4

5}, Yasser Thabet^{1

6}, Prashant V Shinde⁶, Lisa Schmidleithner¹, Maren Köhne¹, Jonel Trebicka⁷, Robert Schierwagen⁷, Andrea Hofmann^{1

8}, Alexey Popov¹, Karl S Lang⁹, Annette Oxenius¹⁰, Thorsten Buch¹¹, Christian Kurts³, Mathias Heikenwalder^{12

13}, Gerd Fätkenheuer^{4

5}, Philipp A Lang^{6

14}, Pia Hartmann^{4

5

15}, Percy A Knolle^{3

16}, Joachim L Schultze^{1

2}

Affiliations

¹ Life and Medical Sciences Bonn, Genomics &Immunoregulation, University of Bonn, Bonn, Germany.
² Platform for Single Cell Genomics and Epigenomics at the German Center for Neurodegenerative Diseases and the University of Bonn, Bonn, Germany.
³ Institute of Experimental Immunology, University Hospital Bonn, Bonn, Germany.
⁴ Department of Internal Medicine I, University Hospital Cologne, Cologne, Germany.
⁵ German Center for Infection Research, partner site Bonn-Cologne, Cologne, Germany.
⁶ Department of Gastroenterology, Hepatology and Infectious Diseases, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany.
⁷ Department of Internal Medicine I, University Hospital Bonn, Bonn, Germany.
⁸ Institute of Human Genetics, Department of Genomics, Life &Brain Center, University of Bonn, Bonn, Germany.
⁹ Institute of Immunology, Faculty of Medicine, University of Duisburg-Essen, Essen, Germany.
¹⁰ Institute of Microbiology, Swiss Federal Institute of Technology Zürich, Zürich, Switzerland.
¹¹ Institute of Laboratory Animal Science, University of Zürich, Schlieren, Switzerland.
¹² Institute of Virology, Technische Universität/Helmholtz Zentrum München, München, Germany.
¹³ Division of Chronic Inflammation and Cancer, German Cancer Research Center, Heidelberg, Germany.
¹⁴ Department of Molecular Medicine II, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany.
¹⁵ Institute for Medical Microbiology, Immunology and Hygiene, University of Cologne, Cologne, Germany.
¹⁶ Institute of Molecular Immunology, Klinikum rechts der Isar, Technische Universität München, München, Germany.

PMID: 26950238
DOI: 10.1038/ni.3399

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adolescent
Adult
Aged
Animals
CD4-Positive T-Lymphocytes / immunology*
CD4-Positive T-Lymphocytes / metabolism
CD4-Positive T-Lymphocytes / virology
Flow Cytometry
HEK293 Cells
HIV / immunology*
HIV / physiology
HIV Infections / genetics
HIV Infections / immunology*
HIV Infections / virology
Host-Pathogen Interactions / immunology
Humans
Immunoblotting
Lymphocytic Choriomeningitis / genetics
Lymphocytic Choriomeningitis / immunology*
Lymphocytic Choriomeningitis / virology
Lymphocytic choriomeningitis virus / immunology*
Lymphocytic choriomeningitis virus / physiology
Mice, Inbred C57BL
Mice, Knockout
Mice, Transgenic
Middle Aged
Oligonucleotide Array Sequence Analysis
Programmed Cell Death 1 Receptor / genetics
Programmed Cell Death 1 Receptor / immunology
Programmed Cell Death 1 Receptor / metabolism
Receptors, Tumor Necrosis Factor / genetics
Receptors, Tumor Necrosis Factor / immunology
Receptors, Tumor Necrosis Factor / metabolism
Reverse Transcriptase Polymerase Chain Reaction
Transcriptome / drug effects
Transcriptome / genetics
Transcriptome / immunology
Tumor Necrosis Factor-alpha / immunology*
Tumor Necrosis Factor-alpha / metabolism
Tumor Necrosis Factor-alpha / pharmacology
Young Adult

Substances

Programmed Cell Death 1 Receptor
Receptors, Tumor Necrosis Factor
Tumor Necrosis Factor-alpha

Associated data

GEO/GSE52185

Grants and funding

HHSN272201300006C/PHS HHS/United States