Differential Regulation of Interleukin-12 (IL-12)/IL-23 by Tim-3 Drives TH17 Cell Development during Hepatitis C Virus Infection

Cytokine production by innate immunity is critical for shaping the adaptive immunity through regulation of T cell differentiation. In this report, we studied T cell immunoglobulin mucin domain protein 3 (Tim-3) expression on monocytes and its regulatory effect on interleukin-12 (IL-12)/IL-23 production by CD14(+) monocytes, as well as IL-17 production by CD4(+) T cells in individuals with chronic hepatitis C virus (HCV) infection. We found that Tim-3 and IL-23p19 are highly expressed and that IL-12p35 is inhibited in human CD14(+) monocytes, while IL-17 expression is upregulated in CD4(+) T cells, in chronically HCV-infected individuals compared to healthy subjects. Interestingly, Tim-3 expression is closely associated with the differential regulation of IL-12/IL-23 expression in CD14(+) monocytes and correlated to IL-17 production by CD4(+) T cells. These Tim-3-associated IL-12/IL-23/IL-17 dysregulations in HCV-infected individuals are also recapitulated in vitro by incubating healthy monocytes or peripheral blood mononuclear cells with Huh-7 hepatoma cells transfected with HCV RNA. Importantly, blocking Tim-3 signaling on monocytes restores the balance of IL-12/IL-23 through the intracellular STAT3 signaling, which in turn reverses the upregulated IL-17 expression both ex vivo and in vitro. Our findings suggest that Tim-3-mediated differential regulation of IL-12/IL-23 drives T(H)17 cell development, a milieu favoring viral persistence and autoimmune phenomenon during HCV infection.