1. Tumor-necrosis factor impairs CD4(+) T cell-mediated immunological control in chronic viral infection.
- Author
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Beyer M, Abdullah Z, Chemnitz JM, Maisel D, Sander J, Lehmann C, Thabet Y, Shinde PV, Schmidleithner L, Köhne M, Trebicka J, Schierwagen R, Hofmann A, Popov A, Lang KS, Oxenius A, Buch T, Kurts C, Heikenwalder M, Fätkenheuer G, Lang PA, Hartmann P, Knolle PA, and Schultze JL
- Subjects
- Adolescent, Adult, Aged, Animals, CD4-Positive T-Lymphocytes metabolism, CD4-Positive T-Lymphocytes virology, Flow Cytometry, HEK293 Cells, HIV physiology, HIV Infections genetics, HIV Infections virology, Host-Pathogen Interactions immunology, Humans, Immunoblotting, Lymphocytic Choriomeningitis genetics, Lymphocytic Choriomeningitis virology, 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 metabolism, Tumor Necrosis Factor-alpha pharmacology, Young Adult, CD4-Positive T-Lymphocytes immunology, HIV immunology, HIV Infections immunology, Lymphocytic Choriomeningitis immunology, Lymphocytic choriomeningitis virus immunology, Tumor Necrosis Factor-alpha immunology
- 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.
- Published
- 2016
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