A crucial role for Kupffer cell-derived galectin-9 in regulation of T cell immunity in hepatitis C infection.
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.
Mengshol
John A
JA
Department of Medicine, Division of Gastroenterology & Hepatology, University of Colorado School of Medicine, Aurora, Colorado, United States of America.
Golden-Mason
Lucy
L
Arikawa
Tomohiro
T
Smith
Maxwell
M
Niki
Toshiro
T
McWilliams
Ryan
R
Randall
Jessica A
JA
McMahan
Rachel
R
Zimmerman
Michael A
MA
Rangachari
Manu
M
Dobrinskikh
Evgenia
E
Busson
Pierre
P
Polyak
Stephen J
SJ
Hirashima
Mitsuomi
M
Rosen
Hugo R
HR
D015704:CD4 Antigens / Q000096:biosynthesis; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism / Q000821:virology; D051858:Forkhead Transcription Factors / Q000096:biosynthesis; D037161:Galectins / Q000378:metabolism*; D015967:Gene Expression Regulation, Viral; D016174:Hepacivirus / Q000378:metabolism*; D006526:Hepatitis C / Q000378:metabolism*; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D007371:Interferon-gamma / Q000378:metabolism; D053645:Interleukin-2 Receptor alpha Subunit / Q000096:biosynthesis; D053699:Interleukin-7 Receptor alpha Subunit / Q000096:biosynthesis; D007728:Kupffer Cells / Q000378:metabolism*; D007963:Leukocytes, Mononuclear / Q000166:cytology; D008024:Ligands; D008264:Macrophages / Q000378:metabolism; D009000:Monocytes / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology*
D015704:CD4 Antigens; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D037161:Galectins; D053645:Interleukin-2 Receptor alpha Subunit; D053699:Interleukin-7 Receptor alpha Subunit; C105032:LGALS9 protein, human; D008024:Ligands; D007371:Interferon-gamma