Differential Regulation of Interleukin-12 (IL-12)/IL-23 by Tim-3 Drives T H 17 Cell Development during Hepatitis C Virus Infection

• Published in: Journal of virology Vol. 87; no. 8; pp. 4372 - 4383
• Main Authors: Wang, Jia M., Shi, Lei, Ma, Cheng J., Ji, Xiao J., Ying, Ruo S., Wu, Xiao Y., Wang, Ke S., Li, Guangyu, Moorman, Jonathan P., Yao, Zhi Q.
• Format: Journal Article
• Language: English
• Published: 15-04-2013
• ISSN: 0022-538X; 1098-5514
• DOI: 10.1128/JVI.03376-12

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.