We thank Roche Basel for providing dihydrofluorouracil chemical standard.
Rapid clonal expansion of CD8+ T cells in response MEK162 ARRY-162 to antigenic challenge is a hallmark of adaptive immunity and a crucial element of host defense. Activation and differentiation of T cells are largely determined by their initial encounter with antigen-presenting cells (APCs), and the resultant responses range from full activation and memory T cell differentiation to clonal exhaustion or deletion, depending on the nature and abundance of inductive signals that T cells decode from APCs during priming [1], [2]. These events generally occur in secondary lymphoid organs because na?ve T cells are usually not primed in nonlymphoid tissues [2].

The liver is, however, an exception to this rule, due to the unique architecture of the hepatic sinusoid which is characterized by a discontinuous endothelium, the absence of a basement membrane, and a very slow flow rate [3]�C[5], allowing circulating T cells to make prolonged direct contact with resident liver cells including hepatocytes [6]. Furthermore, the liver is replete with diverse and unique antigen presenting cell populations, including liver sinusoidal endothelial cells (LSECs) [7], [8], hepatic stellate cells (HSCs) [9], Kupffer cells [10], [11], conventional and plasmacytoid dendritic cells [12]�C[14], all of which are capable of priming and/or tolerizing na?ve T cells, at least in vitro. Thus, because of its unique immunological environment, antigens expressed and/or processed in the liver appear to be more accessible to T cells than those in other nonlymphoid organs [4], [15].

The hepatitis B virus (HBV) is a noncytopathic, enveloped, double-stranded DNA virus that causes acute and chronic hepatitis and hepatocellular carcinoma [16], [17]. Similar to other noncytopathic viruses, the clearance of HBV requires functional virus-specific CD8+ T cell responses [18]. Using the HBV transgenic mouse [19] as a model to study the impact of intrahepatic antigen recognition by HBV-specific CD8+ T cells, we have shown that adoptively transferred HBV-specific memory CD8+ T cells rapidly secrete IFN�� upon antigen recognition in the liver, thereby inhibiting HBV replication [20]. Subsequently, PD-1 is upregulated in the intrahepatic CD8+ T cells and they stop producing IFN��, start expressing granzyme B (GrB) and undergo massive expansion [21] thereby Cilengitide mediating a necroinflammatory liver disease and terminating viral gene expression whereupon the intrahepatic CD8+ T cell population contracts, liver disease abates and IFN�� production returns [21].