HCV -infected hepatocytes drive CD 4 super(+) CD 25 super(+) F oxp3 super(+) regulatory T -cell development through the T im-3/ G al-9 pathway

• Published in: European journal of immunology Vol. 43; no. 2; pp. 458 - 467
• Main Authors: Ji, Xiao J, Ma, Cheng J, Wang, Jia M, Wu, Xiao Y, Niki, Toshiro, Hirashima, Mitsumi, Moorman, Jonathan P, Yao, Zhi Q
• Format: Journal Article
• Language: English
• Published: 01-02-2013
• Subjects: Hepatitis C virus
• ISSN: 0014-2980; 1521-4141
• DOI: 10.1002/eji.201242768

HCV is remarkable at disrupting human immunity to establish chronic infection. The accumulation of T reg cells at the site of infection and upregulation of inhibitory signaling pathways (such as T-cell Ig and mucin domain protein-3 ( T im-3) and galectin-9 ( G al-9)) play pivotal roles in suppressing antiviral effector T ( T eff) cells that are essential for viral clearance. While T im-3/ G al-9 interactions have been shown to negatively regulate T eff cells, their role in regulating T reg cells is poorly understood. To explore how T im-3/ G al-9 interactions regulate HCV -mediated T reg-cell development, here we provide pilot data showing that HCV -infected human hepatocytes express higher levels of G al-9 and TGF -[beta], and upregulate T im-3 expression and regulatory cytokines TGF -[beta]/ IL -10 in co-cultured human CD 4 super(+) T cells, driving conventional CD 4 super(+) T cells into CD 25 super(+) F oxp3 super(+) T reg cells. Additionally, recombinant G al-9 protein can transform TCR -activated CD 4 super(+) T cells into F oxp3 super(+) T reg cells in a dose-dependent manner. Importantly, blocking T im-3/ G al-9 ligations abrogates HCV -mediated T reg-cell induction by HCV -infected hepatocytes, suggesting that T im-3/ G al-9 interactions may regulate human F oxp3 super(+) T reg-cell development and function during HCV infection.