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A crucial role for Kupffer cell-derived galectin-9 in regulation of T cell immunity in hepatitis C infection. PLoS One 2010 Mar 04;5(3):e9504

Date

03/09/2010

Pubmed ID

20209097

Pubmed Central ID

PMC2831996

DOI

10.1371/journal.pone.0009504

Scopus ID

2-s2.0-77949793555   139 Citations

Abstract

Approximately 200 million people throughout the world are infected with hepatitis C virus (HCV). One of the most striking features of HCV infection is its high propensity to establish persistence (approximately 70-80%) and progressive liver injury. Galectins are evolutionarily conserved glycan-binding proteins with diverse roles in innate and adaptive immune responses. Here, we demonstrate that galectin-9, the natural ligand for the T cell immunoglobulin domain and mucin domain protein 3 (Tim-3), circulates at very high levels in the serum and its hepatic expression (particularly on Kupffer cells) is significantly increased in patients with chronic HCV as compared to normal controls. Galectin-9 production from monocytes and macrophages is induced by IFN-gamma, which has been shown to be elevated in chronic HCV infection. In turn, galectin-9 induces pro-inflammatory cytokines in liver-derived and peripheral mononuclear cells; galectin-9 also induces anti-inflammatory cytokines from peripheral but not hepatic mononuclear cells. Galectin-9 results in expansion of CD4(+)CD25(+)FoxP3(+)CD127(low) regulatory T cells, contraction of CD4(+) effector T cells, and apoptosis of HCV-specific CTLs. In conclusion, galectin-9 production by Kupffer cells links the innate and adaptive immune response, providing a potential novel immunotherapeutic target in this common viral infection.

Author List

Mengshol JA, Golden-Mason L, Arikawa T, Smith M, Niki T, McWilliams R, Randall JA, McMahan R, Zimmerman MA, Rangachari M, Dobrinskikh E, Busson P, Polyak SJ, Hirashima M, Rosen HR

Author

Michael A. Zimmerman MD, FACS Professor in the Surgery department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

CD4 Antigens
CD4-Positive T-Lymphocytes
Forkhead Transcription Factors
Galectins
Gene Expression Regulation, Viral
Hepacivirus
Hepatitis C
Humans
Immunotherapy
Interferon-gamma
Interleukin-2 Receptor alpha Subunit
Interleukin-7 Receptor alpha Subunit
Kupffer Cells
Leukocytes, Mononuclear
Ligands
Macrophages
Monocytes
T-Lymphocytes
jenkins-FCD Prod-486 e3098984f26de787f5ecab75090d0a28e7f4f7c0