Nat Immunol. 2016 May; 17(5):593-603.

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

Beyer M, Abdullah Z, Chemnitz JM, Maisel D, Sander J, Lehmann C, Thabet Y, SHinde PV, Schmidleithner L, Köhne M, Fätkenheuer G, Lang PA, Hartmann P, Knolle PA, Schultze JL.

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.