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

作为一种基本的HLH-PAS转录因子，缺氧诱导因子-1α (HIF-1α)通过调节参与葡萄糖摄取、血管生成、红细胞生成和细胞存活的基因，促进细胞对缺氧的适应。当T细胞从淋巴结或循环系统迁移到外周炎症部位进行免疫反应时，它们必须适应并在比循环系统低得多的氧张力下发挥作用。为了研究HIF-1α在体内外周T细胞中的作用，我们将HIF-1α修饰的小鼠与近端缺失启动子驱动的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细胞在胸腺中正常生成，并在脾脏中分布，淋巴结未受损。在里面。在体外培养条件下，HIF-1α-缺陷T细胞在抗cd3抗体或Con a刺激下表现出不减少的IL-2/IL-2R的产生和增殖…更多在本财政年度，我们研究了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/巨噬细胞和T细胞介导的炎症过程在动脉粥样硬化和血管重构中起作用。hif -1 α也被证明与T细胞功能有关；然而，其在炎症和血管重构中的作用尚不清楚。使用该模型将使我们了解T细胞中的HIF-1α如何在体内促进免疫反应。与对照组相比，袖带植入引起HIF-1α KO小鼠明显的新内膜增生（袖带置换术的HIF-1α KO小鼠的内膜/中膜<内膜/管腔>比值：0.28 <0.31>，未袖带置换术的HIF-1α KO小鼠的0.07 <0.06>）。然而，在WT和ARNT - KO小鼠中，袖带损伤的血管重构没有明显加剧。H&E染色显示HIF-1α KO小鼠外膜的单核细胞（包括浆细胞）浸润显著增加，而WT小鼠和ARNT KO小鼠仅轻微增加。T细胞中的HIF-1信号通路在动脉硬化的进展中起着至关重要的作用。了解HIF-1信号通路参与动脉粥样硬化的分子机制，将为开发抗动脉粥样硬化新药提供治疗靶点。少

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