title: Differential regulation of interleukin-12 (IL-12)/IL-23 by Tim-3 drives T(H)17 cell development during hepatitis C virus infection.
abstract: 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.
authors: Hepatitis (HCV/HIV) Program, James H. Quillen VA Medical Center, Department of Veterans Affairs, Johnson City, Tennessee, USA.
authors: Jia M
authors: JM
authors: Wang
authors: Lei
authors: L
authors: Shi
authors: Cheng J
authors: CJ
authors: Ma
authors: Xiao J
authors: XJ
authors: Ji
authors: Ruo S
authors: RS
authors: Ying
authors: Xiao Y
authors: XY
authors: Wu
authors: Ke S
authors: KS
authors: Wang
authors: Guangyu
authors: G
authors: Li
authors: Jonathan P
authors: JP
authors: Moorman
authors: Zhi Q
authors: ZQ
authors: Yao
mesh_terms: D002454:Cell Differentiation; D000072597:Hepatitis A Virus Cellular Receptor 2; D019698:Hepatitis C, Chronic / Q000276:immunology*; D006801:Humans; D018664:Interleukin-12 / Q000096:biosynthesis*; D053759:Interleukin-23 / Q000096:biosynthesis*; D016131:Lymphocyte Subsets / Q000276:immunology / Q000502:physiology; D008565:Membrane Proteins / Q000378:metabolism*; D058504:Th17 Cells / Q000276:immunology* / Q000502:physiology
chemical_list: C448908:HAVCR2 protein, human; D000072597:Hepatitis A Virus Cellular Receptor 2; D053759:Interleukin-23; D008565:Membrane Proteins; D018664:Interleukin-12
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