A crucial role for Kupffer cell-derived galectin-9 in regulation of T cell immunity in hepatitis C infection.
A crucial role for Kupffer cell-derived galectin-9 in regulation of T cell immunity in hepatitis C infection.
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DOI：
10.1371/journal.pone.0009504
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发表时间：
2010-03-04
期刊：
影响因子：
3.7
通讯作者：
Rosen HR
中科院分区：
文献类型：
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作者：
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
全世界约有2亿人感染丙型肝炎病毒（HCV）。HCV感染的最显著特征之一是其高倾向性建立持续性（约70-80%）和进行性肝损伤。半乳糖凝集素是进化上保守的聚糖结合蛋白，在先天性和适应性免疫应答中具有不同的作用。在这里，我们证明了半乳糖凝集素-9，T细胞免疫球蛋白结构域和粘蛋白结构域蛋白3（Tim-3）的天然配体，在血清中以非常高的水平循环，其肝脏表达（特别是在库普弗细胞上）在慢性HCV患者中与正常对照组相比显着增加。IFN-γ诱导单核细胞和巨噬细胞产生半乳糖凝集素-9，已显示IFN-γ在慢性HCV感染中升高。反过来，半乳糖凝集素-9在肝源性和外周单核细胞中诱导促炎细胞因子;半乳糖凝集素-9还从外周单核细胞而不是肝单核细胞诱导抗炎细胞因子。半乳糖凝集素-9导致CD 4 + CD 25 + FoxP 3 + CD 127低调节性T细胞的扩增、CD 4+效应T细胞的收缩和HCV特异性CTL的凋亡。总之，半乳糖凝集素-9生产的库普弗细胞连接先天性和适应性免疫反应，提供了一个潜在的新的免疫靶点，在这种常见的病毒感染。
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 (∼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-γ, 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+CD127low 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.