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.

Background/Aims: Similar to apoptosis of nucleated cells, red blood cells (RBC) can undergo suicidal cell death - called eryptosis. It is characterized by cell shrinkage and phosphatidylserine translocation. Eryptosis is triggered by an increase of intracellular calcium concentration due to activation of nonselective cation channels. The cation channels and consequently eryptosis are inhibited by erythropoietin. Eryptotic RBC are engulfed by macrophages and thus rapidly cleared from circulating blood. In this study, we explored whether storage of RBC influences the rate of eryptosis. Methods: Flow cytometry was employed to quantify phosphatidylserine exposing erythrocytes from annexin V binding and cytosolic Ca²⁺ activity from Fluo-3 fluorescence. Clearance of stored murine RBC was tested by injection of carboxyfluorescein succinimidyl ester (CFSE)-labelled erythrocytes. Results: Storage for 42 days significantly increased the percentage of phosphatidylserine exposing and haemolytic erythrocytes, an effect blunted by removal of extracellular calcium. Phosphatidylserine exposure could be inhibited by addition of erythropoietin. Upon transfusion, the clearance of murine CFSE-labelled RBC from circulating blood was significantly higher following storage for 10 days when compared to 2 days of storage. Conclusion: Storage of RBC triggers eryptosis by Ca²⁺ and erythropoietin sensitive mechanisms.

During viral infection, tight regulation of CD8 + T-cell functions determines the outcome of the disease. Recently, others and we determined that the natural killer (NK) cells kill hyperproliferative CD8 + T cells in the context of viral infection, but molecules that are involved in shaping the regulatory capability of NK cells remain virtually unknown. Here we used mice lacking the Fc-receptor common gamma chain (FcRγ, FcεRIγ, Fcer1g –/– mice) to determine the role of Fc-receptor and NK-receptor signaling in the process of CD8 + T-cell regulation. We found that the lack of FcRγ on NK cells limits their ability to restrain virus-specific CD8 + T cells and that the lack of FcRγ in Fcer1g –/– mice leads to enhanced CD8 + T-cell responses and rapid control of the chronic docile strain of the lymphocytic choriomeningitis virus (LCMV). Mechanistically, FcRγ stabilized the expression of NKp46 but not that of other killer cell–activating receptors on NK cells. Although FcRγ did not influence the development or activation of NK cell during LCMV infection, it specifically limited their ability to modulate CD8 + T-cell functions. In conclusion, we determined that FcRγ plays an important role in regulating CD8 + T-cell functions during chronic LCMV infection.

Nuclear pRelA translocation in hepatocytes Highlights LCMV infection activates NF-jB signaling in hepatocytes. Macrophages, TNFR1 signaling do not induce LCMV-driven hepatocyte NF-jB-activation. Ikkb DHep mice display increased viral infection/replication and lower ISG induction. Ifnar DHep mice recapitulate aberrant virus replication as observed in Ikkb DHep mice. NF-jB signaling is required for efficient ISG induction in HBV-/HDV-infected HepaRG.

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