Upregulation of SOCS-3 and PIAS-3 impairs IL-12-mediated interferon-gamma response in CD56+ T cells in HCV-infected heroin users

Abstract

Background: CD56+ T cells are abundant in liver and play an important role in host innate immunity against viral infections, including hepatitis C virus (HCV) infection, a common infection among heroin abusers. We thus investigated the in vivo impact of heroin use or heroin use plus HCV infection on the CD56+ T cell frequency and function. Methodology/Principal Findings: A total of 37 heroin users with (17) or without (20) HCV infection and 17 healthy subjects were included in the study. Although there was no significant difference in CD56+ T cell frequency in PBMCs among three study groups, CD56+ T cells isolated from the heroin users had significantly lower levels of constitutive interferon-gamma (IFN-γ) expression than those from the normal subjects. In addition, when stimulated by interleukin (IL)-12, CD56+ natural T cells from HCV-infected heroin users produced significantly lower levels of IFN-γ than those from the normal subjects. This diminished ability to produce IFN-γ by CD56+ T cells was associated with the increased plasma HCV viral loads in the HCV-infected heroin users. Investigation of the mechanisms showed that although heroin use or heroin use plus HCV infection had little impact on the expression of the key positive regulators (IL-12 receptors, STAT-1, 3, 4, 5, JAK-2, and TYK-2) in IL-12 pathway, heroin use or heroin use plus HCV infection induced the expression of suppressor of cytokine signaling protein-3 (SOCS-3) and protein inhibitors of activated STAT-3 (PIAS-3), two key inhibitors of IL-12 pathway. Conclusion/Significance: These findings provide compelling in vivo evidence that heroin use or heroin use plus HCV infection impairs CD56+ T cell-mediated innate immune function, which may account for HCV infection and persistence in liver. © 2010 Ye et al.