Spatiotemporal dynamics and genomic landscape of CD8+ T cells undergoing intrahepatic priming

CD8+ T cell responses to hepatotropic viruses like HBV range from dysfunction to differentiation into effector cells, but the mechanisms underlying these distinct outcomes remain poorly understood. Here we show that priming by Kupffer cells –not natural targets of HBV – leads to differentiation into effector cells that form dense, extravascular clusters of rather immotile cells scattered throughout the liver. By contrast, priming by hepatocytes – natural targets of HBV – leads to local activation and proliferation but lack of differentiation into effector cells; these cells form loose, intravascular clusters of motile cells that coalesce around portal tracts. Transcriptomic and chromatin accessibility analyses unveil unique features of these dysfunctional CD8+ T cells, with limited overlap with those of exhausted or tolerant T cells; accordingly, CD8+ T cells primed by hepatocytes cannot be rescued by anti-PD-L1 treatment, but instead respond to IL-2. These findings suggest new immunotherapeutic strategies against chronic HBV infection.