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Distribution and function of IL-7-producing cells

IL-7产生细胞的分布和功能

基本信息

批准号：
21590531
负责人：
IKUTA Koichi
金额：
$ 3万
依托单位：
Kyoto University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2009
资助国家：
日本
起止时间：
2009 至 2011
项目状态：
已结题

项目摘要

IL-7 is an essential cytokine for lymphocyte development and survival produced by mesenchymal and epithelial cells in lymphoid organs. However, little is known about the precise nature and distribution of IL-7-expressing cells in vivo. To address this question, we established IL-7-GFP knock-in mice. We found that GFP is expressed in bone marrow stromal cells, thymic epithelial cells(TECs), fibroblastic reticular cells(FRCs) and lymphatic endothelial cells in lymph nodes, and intestinal epithelial cells. After induction of acute colitis with DSS, GFP expression was elevated in the intestinal epithelial cells. Thus, the IL-7-GFP knock-in mouse reveals unreported types of IL-7-expressing cells and provides a powerful tool to analyze the IL-7-niche in the lymphoid organs under physiological and pathological conditions. We next established IL-7-floxed mice and crossed with FoxN1-Cre transgenic(Tg) mice to obtain the conditional knockout mice deficient in IL-7 production from TECs. FoxN1-Cre … More IL-7flox/flox mice showed severely reduced numbers of total andγδT cells in the thymus. These results suggested that IL-7 produced by TECs plays a major role in proliferation, survival, and maturation of thymocytes. In small intestine, cell numbers ofγδIELs were significantly reduced in FoxN1-Cre IL-7flox/flox mice, suggesting that IL-7 produced in the thymus is essential forγδIEL development. Thus, this study presents strong evidence for the thymic originγδIELs. We next crossed IL-7-floxed mice with albumin promoter-driven Cre(Alb-Cre) Tg mice to establish conditional knockout of IL-7 in hepatocytes. We found that NKT and T cells were moderately decreased in adultliver of IL-7f/f Alb-Cre mice and that B cell development was impaired in perinatal liver of IL-7f/f Alb-Cre mice. This study demonstrates that hepatocyte-derived IL-7 plays an indispensable role in maintenance of NKT and T cells in adult liver and development of B cells in fetal liver and suggests that hepatocytes provide a unique IL-7 niche for intrahepatic lymphocytes. Less

IL-7是淋巴器官中的间充质细胞和上皮细胞产生的淋巴细胞发育和存活所必需的细胞因子。然而，很少有人知道IL-7表达细胞在体内的确切性质和分布。为了解决这个问题，我们建立了IL-7-GFP基因敲入小鼠。我们发现GFP在骨髓基质细胞、胸腺上皮细胞（TEC）、成纤维网状细胞（FRC）和淋巴结中的淋巴管内皮细胞以及肠上皮细胞中表达。DSS诱导急性结肠炎后，肠上皮细胞中GFP表达升高。因此，IL-7-GFP敲入小鼠揭示了未报道的IL-7表达细胞的类型，并提供了一个强大的工具来分析在生理和病理条件下淋巴器官中的IL-7-生态位。我们接下来建立IL-7-floxed小鼠并与FoxN 1-Cre转基因（Tg）小鼠杂交以获得TEC产生IL-7缺陷的条件性敲除小鼠。FoxN1-Cre ...更多信息 IL-7 flox/flox小鼠显示胸腺中总T细胞和γδT细胞数量严重减少。这些结果表明，由TEC产生的IL-7在胸腺细胞的增殖、存活和成熟中起主要作用。在小肠中，FoxN 1-Cre IL-7 flox/flox小鼠中γδ IEL的细胞数量显著减少，表明胸腺中产生的IL-7对γδIEL的发育至关重要。因此，本研究为胸腺源性γδ IEL提供了强有力的证据。我们接下来将IL-7-floxed小鼠与白蛋白启动子驱动的Cre（Alb-Cre）Tg小鼠杂交，以建立肝细胞中IL-7的条件性敲除。我们发现IL-7 f/f Alb-Cre小鼠的成年肝脏中NKT和T细胞中度减少，IL-7 f/f Alb-Cre小鼠的围产期肝脏中B细胞发育受损。这项研究表明，肝细胞来源的IL-7在维持成人肝脏中的NKT和T细胞以及胎儿肝脏中的B细胞的发育中起着不可或缺的作用，并表明肝细胞为肝内淋巴细胞提供了独特的IL-7生态位。少