Hepatitis C viral infection is associated with activated cytolytic natural killer cells expressing high levels of T cell immunoglobulin- and mucin-domain-containing molecule-3.

- Tim-3 is increased on NK cells in chronic Hepatitis C viral infection.
- Tim-3 expression on NK cells is associated with an activated phenotype.
- Tim-3high NKs are polarized towards cytotoxicity.
- Tim-3high NKs might represent targets for treatment of chronic viral infections.

T cell immunoglobulin- and mucin-domain-containing molecule-3 (Tim-3) is an inhibitory receptor implicated in T cell exhaustion characteristic of chronic viral infection. Limited data exist on NK cell Tim-3 expression and functional consequences. In chronic hepatitis C virus (HCV)-infected subjects, we found increased Tim-3 on NKs, which was associated with an activated phenotype. The high level of Tim-3 was not reversed by successful IFN-alpha-based antiviral therapy. Tim-3high NK cells up-regulated TRAIL in response to IFN-alpha to a greater extent and demonstrated greater lymphokine-activated killing activity, viral control, and degranulation but similar cytokine production than their Tim-3low counterparts. Our results suggest that Tim-3 on NKs is associated with activation of this innate lymphocyte population that is polarized towards cytotoxicity in chronic HCV. These findings reveal roles for Tim-3 in the regulation of NKs that might represent targets for treatment of chronic viral infections.

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