The Tim-3/galectin-9 pathway involves in the homeostasis of hepatic Tregs in a mouse model of concanavalin A-induced hepatitis
The Tim-3/galectin-9 pathway involves in the homeostasis of hepatic Tregs in a mouse model of concanavalin A-induced hepatitis
复制标题
Tim-3/galectin-9 通路参与刀豆球蛋白 A 诱导的肝炎小鼠模型中肝脏 Tregs 的稳态。
DOI：
10.1016/j.molimm.2013.11.001
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发表时间：
2014-03-01
影响因子：
3.6
通讯作者：
Zou, Jianwen
中科院分区：
文献类型：
--
作者：
Ju, Ying;Shang, Xuming;Zou, Jianwen
T细胞免疫球蛋白和粘蛋白结构域包含分子3（Tim-3）是分泌干扰素（IFN）-γ的CD 4（+）Th 1细胞的负调节剂，并且在自身免疫性疾病中起关键作用。在此，我们报道了伴刀豆球蛋白A（Con A）诱导的肝炎小鼠模型中，肝CD 4（+）CD 25（+）T细胞中半乳糖凝集素-9的表达增加。此外，Tim-3在CD 4（+）CD 25（+）Foxp 3（+）调节性T细胞（TCFs）中显示出增加的水平。进一步的分析显示，阻断Tim-3/半乳糖凝集素-9途径导致体外Teff的抑制，从而显著增加肝Teff的干扰素（IFN）-γ产生。此外，用抗Tim-3抗体在体内阻断Tim-3可能通过增加IFN-γ产生而加重急性肝炎。此外，我们发现，在体外活化的CD 4（+）CD 25（-）T细胞与T细胞受体（TCR）加白细胞介素2（IL-2）上调Tim-3的表达。诱导的Tim-3与galectin-9相互作用，诱导CD 4 + T细胞凋亡，阻断Tim-3信号通路可部分逆转这种凋亡。我们的研究结果表明，Tim-3/galectin-9途径通过消除诱导Teffs和抑制IFN-γ的释放，在肝Tfos的稳态中起着关键作用，这有助于肝损伤的发病机制，并构成Con A诱导肝炎的机制的至少一部分。(C)2013爱思唯尔有限公司保留所有权利。
T cell immunoglobulin- and mucin-domain-containing molecule-3 (Tim-3) is a negative regulator of interferon (IFN)-gamma-secreting CD4(+) Th1 cells and plays a key role in autoimmune diseases. Here, we report that galectin-9 expression was increased in hepatic CD4(+)CD25(+) T cells in a mouse model of concanavalin A (Con A)-induced hepatitis. Moreover, Tim-3 showed increased levels in CD4(+)CD25(+) Foxp3(+) regulatory T cells (Tregs). Further analyses showed that blocking the Tim-3/galectin-9 pathway resulted in the suppression of Tregs in vitro, thereby significantly increasing interferon (IFN)-gamma production from hepatic Teffs. Moreover, blockade of Tim-3 in vivo with an anti-Tim-3 antibody exacerbated the acute hepatitis, possibly by increased IFN-gamma production. Furthermore, we found that in vitro activation of CD4(+)CD25(-) T cells with the T cell receptor (TCR) plus interleukin 2 (IL-2) up-regulated Tim-3 expression. And the induced Tim-3 interacted with galectin-9 to induce CD4(+) T cell apoptosis which could be partly reversed by blocking Tim-3 signaling. Our results suggested that the Tim-3/galectin-9 pathway plays a critical role in the homeostasis of hepatic Tregs through the elimination induction in Teffs and the inhibition of IFN-gamma release, which contributes to the pathogenesis of liver damage and constitutes at least part of the mechanism underlying the induction of hepatitis by Con A. (C) 2013 Elsevier Ltd. All rights reserved.