Journal Article

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

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

2016

Overview

Functional T cell exhaustion occurs during chronic viral infection or in tumor settings. Beyer et al . report that chronic inflammation mediated by the cytokine TNF is responsible for this dysfunction and that blockade of this pathway restores immune system–mediated control of viral infection. 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.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 38 / 38/39 / 38/61 / 631/250/1619/554/1898 / 631/250/254 / 64/60 / 692/699/255/1901 / 692/699/255/2514 / Adolescent / Adult / Aged / Animals / Biomedicine / 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 / Immunology / Infectious Diseases / 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