Tetherin controls T cell proliferation and exhaustion by shaping the early distribution of a persistent viral infection

Abstract

Abstract Type I interferons participate in the host defense against most viral infections through induction of innate antiviral proteins like tetherin (BST-2). In vitro studies have shown that tetherin can physically sequester viruses by linking them to infected cells, which in turn reduces virion release. It is not currently understood how this antiviral protein functions in vivo to control an immune response mounted against a persistent viral infection. We sought novel mechanistic insights into the function of tetherin by studying its role in the establishment of a persistent lymphocytic choriomeningitis virus (LCMV) infection. Following viral infection, tetherin was significantly upregulated in B cells, plasmacytoid dendritic cells (DCs), conventional DCs, and brain-resident microglia. Genetic deletion of tetherin resulted in an early failure to contain a persistence-prone strain of LCMV in the splenic marginal zone. This resulted in a rapid re-distribution of LCMV into the red and white pulp at early time points post-infection. This also interfered with the early priming of antiviral T cells by causing them to localize preferentially to the splenic red pulp where they proliferated less and acquired an impaired phenotype characterized by upregulation of exhaustion markers (PD-1, LAG-3, TIGIT), loss of cytokine production, and decreased motility. Importantly, these early alterations impeded the ability of the host to control persistence-prone LCMV. Viral control was delayed in peripheral tissues, and lifelong persistence was established in the brain. These data demonstrate that tetherin plays a critical in vivo role in shaping the anatomical distribution and adaptive immune response against a persistent viral infection.