Indeed, the literature reveals significant differences between na?ve and memory CD8+ T cells in terms of the peptide:MHC complex concentration and costimulation required for activation Bioactive compound and the development of their proliferative and cytokine secretion potentials, cytolytic activity and their migratory range [2], [22]. While T cell priming to viruses that do not infect conventional pAPCs is believed to occur in lymphoid organs via cross-priming [1], [2], [23], [24], the consequences of na?ve T cell priming by hepatocellularly expressed viral antigen are less well understood. In the current study, we used transgenic mice whose CD8+ T cells express T cell receptors (TCRs) specific for the HBV nucleocapsid (COR) and envelope (ENV) proteins to study the early intrahepatic immunological events that are likely to occur during HBV infection.

By analyzing the response of na?ve COR- and ENV-specific TCR transgenic CD8+ T cells to hepatocellularly presented HBV antigens in vivo after adoptive transfer into HBV transgenic mice whose hepatocytes produce all the HBV gene products and secrete infectious HBV virions [19], and in vitro after cocultivation with primary HBV transgenic mouse hepatocytes, we show that HBV-specific na?ve CD8+ T cells are primed in the liver by HBV+ hepatocytes and proliferate vigorously in situ, but do not differentiate into functional effector T cells unless PD-1 signaling is genetically ablated. Importantly, when the same T cells are transferred into HBV transgenic mice whose myeloid dendritic cells (mDCs) were simultaneously activated by agonistic antibodies against CD40 (��CD40), PD-1 induction is suppressed and the T cells differentiate normally, inhibit HBV antigen expression, and cause liver disease.

Collectively, these results indicate that CD40-mediated activation of mDCs can rescue the effector functions of PD-1-inhibited na?ve CD8+ T cells, apparently by suppressing the negative regulatory signals that are triggered by antigen recognition in the liver. These results imply that the balance achieved between these two opposing forces may regulate GSK-3 the pathogenesis and outcome of HBV and other hepatotropic virus infections. Results Generation of HBV COR93-specific and ENV28-specific TCR transgenic mice A Kb-restricted CD8+ CTL clone (BC10) that recognizes an epitope located between residues 93�C100 in the HBV core protein (MGLKFRQL) (COR93) was generated from a Balb/c (H-2d) by C57BL/6 (H-2b) F1 hybrid (CB6F1) mouse that was immunized by standard DNA-prime/vaccinia boost immunization as previously described [21], [25]. Importantly, when in vitro core peptide-activated BC10 T cells (1��107/mouse) were adoptively transferred into HBV transgenic mice (lineage 1.3.