The roles of HIF-1α in T cell-dependent immune responses

HIF-1α 在 T 细胞依赖性免疫反应中的作用

基本信息

批准号：
17590436
负责人：
TOMITA Shuhei
金额：
$ 1.98万
依托单位：
The University of Tokushima
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2006
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17590436/
关键词：
Hypoxia T cell HIF-1 immune responses knock out

项目摘要

A basic HLH-PAS transcription factor, hypoxia inducible factor-1α (HIF-1α) facilitates the adaptation of cells to oxygen deprivation, by regulating the genes that are involved in glucose uptake, angiogenesis, erythropoiesis, and cell survival. When T cells migrate from lymph node or the circulation to peripheral inflammation site for immune response, they should be required to adapt to and function within oxygen tensions much lower than those encountered in circulation system. To investigate the role of HIF-1α in peripheral T cells in vivo, we generated T cell-specific HIF-1α KO mice by crossing HIF-1α floxed mice with proximal lck promoter-driven Cre-transgenic mice. We found that HIF-1α-KO T cells were normally generated in the thymus and their distribution in the spleen, and lymph nodes was unimpaired. In the in. vitro culture conditions, HIF-1α-deficient T cells exhibited undiminished IL-2/IL-2R production and proliferation upon stimulation with either anti-CD3 antibody or Con A. I … More n this fiscal year, we have examined whether T cell-mediated responses in HIF-1α KO mice also show consistent results to in vitro experiment described above.The inflammatory process mediated by monocytes/macrophages and T cells plays a role in atherosclerosis and vascular remodeling. HIF-1alpha has also been shown to be related to T cell functions; however, its role in inflammation and vascular remodeling still unknown clearly. To use this model would lead to us how HIF-1α in T cells contributes to immune response in vivo.Cuff placement caused significant neointimal hyperplasia in HIF-1α KO mice compared with the control (intima/media< intima/lumen > ratio: 0.28 <0.31> in HIF-1α KO mice with cuff replacement vs. 0.07 <0.06> in those without cuff replacement). However, there was no obvious exacerbation of cuff-injured vascular remodeling in WT and ARNT KO mice. H＆E staining showed that infiltration of mononuclear cells, including plasma cells, at the adventitia was remarkably increased in HIF-1α KO mice but increased only slightly in WT mice and ARNT KO mice.The HIF-1 signaling pathway in T cells plays a crucial role in the progression of arteriosclerosis. Understanding the molecular mechanism of how HIF-1 signaling pathway is involved in atherosclerosis will provide a therapeutic target for the development of new drugs against atherosclerosis. Less

缺氧诱导因子 1α (HIF-1α) 是一种基本的 HLH-PAS 转录因子，通过调节 T 细胞迁移时参与葡萄糖摄取、血管生成、红细胞生成和细胞存活的基因，促进细胞适应缺氧。从淋巴结或循环系统到周围炎症部位进行免疫反应，它们应该需要适应比循环系统低得多的氧张力并发挥作用，以研究 HIF-1α 的作用。在体内外周 T 细胞中，我们通过将 HIF-1α floxed 小鼠与近端 lck 启动子驱动的 Cre 转基因小鼠杂交，产生了 T 细胞特异性 HIF-1α KO 小鼠，我们发现 HIF-1α-KO T 细胞通常在体内产生。胸腺及其在脾脏和淋巴结中的分布未受损。在体外培养条件下，HIF-1α 缺陷的 T 细胞表现出 IL-2/IL-2R 的产生未减少。抗 CD3 抗体或 Con A 刺激后的增殖和增殖。在本财年，我们检查了 HIF-1α KO 小鼠中 T 细胞介导的反应是否也显示出与上述体外实验一致的结果。单核细胞/巨噬细胞和 T 细胞介导的过程在动脉粥样硬化和血管重塑中发挥作用，也已被证明与 T 细胞功能有关；然而，其在炎症和血管重塑中的作用仍不清楚。使用该模型将引导我们了解T细胞中的HIF-1α如何促进体内免疫反应。与对照组相比，袖带放置引起HIF-1α KO小鼠显着的新内膜增生（内膜/中膜<内膜/内腔>比率：0.28更换袖带的 HIF-1α KO 小鼠为 <0.31>，而未更换袖带的小鼠则为 0.07 <0.06>。 H&E 染色显示，HIF-1α KO 小鼠外膜处的单核细胞（包括浆细胞）浸润显着增加，但 WT 小鼠和 ARNT KO 小鼠仅略有增加。 .T细胞中的HIF-1信号通路在动脉硬化的进展中发挥着至关重要的作用。了解HIF-1信号通路参与动脉硬化的分子机制。动脉粥样硬化将为开发抗动脉粥样硬化新药提供治疗靶点。