14 Interestingly, in vitro blockade of CTLA-4 or PD-1 alone did not increase the proliferative capacity or antiviral cytokine production of HCV-specific T cells; however, improvement of these functions occurred when blockade of both pathways was combined,14 consistent with a role for multiple such mediators in CD8 T cell dysfunction and reinforcing the need for exploration of further potential negative regulators of HCV-specific T cell function. Rosen and colleagues have shown that expression of the inhibitory ligand T cell immunoglobulin Vorinostat price and mucin-domain–containing molecule-3

(Tim-3) is increased on CD4 and CD8 T cells in chronic HCV infection.15 Tim-3 expression by HCV-specific CD8 T cells correlated with an exhausted phenotype and decreased cytokine production. Interestingly, the highest proportion of dual Tim-3/PD-1–expressing HCV-specific CD8 T cells was observed in the liver,15 in which high levels of the Tim-3 ligand galectin-9 are expressed in persistent HCV infection, especially by Kupffer cells.16 These findings have been further explored by Rosen and coworkers in

their recent publication.17 In this work, they describe a number of important findings linking Tim-3 and Tim-3/PD-1 coexpression to infection outcome in acute infection, and to potentially reversible HCV-specific CD8 T cell exhaustion in chronic HCV infection. Interestingly, although whether the level of PD-1 expression by virus-specific CD8 T cells during acute hepatitis C predicts the outcome of infection remains controversial, Stem Cell Compound Library molecular weight they found in the acute phase of infection that Tim-3 expression by HCV-specific CD8 T cells was lower in those subjects with acute resolving infection than that seen in individuals evolving to chronic infection. Furthermore, although the proportion of

exhausted dual Tim-3/PD-1–expressing HCV-specific CD8 T cells was less than that of more functional dual Tim-3–negative/PD-1–negative cells in those individuals resolving infection, a higher ratio of the dual positive exhausted cells to the dual negative functional cells was seen in those subjects who developed chronic infection. As well as holding potential to aid the prediction of viral clearance in Levetiracetam acute infection, these results imply that Tim-3–related pathways function relatively early in determining infection outcome. In addition to their findings in acute HCV infection, Rosen et al. undertook further study of the functional implications of Tim-3 expression and Tim-3/PD-1 coexpression, as well as the effects of blockade of these pathways.17 These experiments confirmed poor production of antiviral cytokines by Tim-3–expressing HCV-specific CD8 T cells, with increasing dysfunction associated with higher levels of Tim-3 expression. Blockade of Tim-3, as previously demonstrated with PD-1 inhibition, was shown to increase in vitro proliferation of HCV-specific CD8 T cells.