Hypoxia controls CD4+CD25+ regulatory T-cell homeostasis via hypoxia-inducible factor-1α
Hypoxia controls CD4+CD25+ regulatory T-cell homeostasis via hypoxia-inducible factor-1α
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DOI：
10.1002/eji.200838318
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发表时间：
2008-09-01
影响因子：
5.4
通讯作者：
George, Jacob
中科院分区：
文献类型：
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作者：
Ben-Shoshan, Jeremy;Maysel-Auslender, Sophia;George, Jacob
最近的数据表明，缺氧及其主要分子特征 HIF-1（缺氧诱导因子-1）可能通过控制抗炎程序来调节炎症。我们测试了缺氧和 HIF-1 α 对天然调节性 T 细胞 (Treg) 及其转录激活剂 Foxp3 稳态的影响。缺氧会导致小鼠和人类 T 细胞中 HIF-1 α 的时间依赖性增加。缺氧上调 Jurkat T 细胞、人和鼠单核细胞中 Foxp3 的表达。缺氧对 Foxp3 表达的影响是 HIF-1 α 依赖性的，因为在转染 HIF-1 α 的短干扰 RNA 后，这些影响被消除，并被 HIF-1 α 过表达所促进。缺氧增加了Treg的效力，因为缺氧的CD4(+)CD25(+)淋巴细胞比常氧细胞更能有效地抑制CD4(+)CD25(-)效应子的增殖。通过流体动力学注射各自的裸DNA实现的HIF-1α的体内表达同样诱导Foxp3表达的增加和功能活性Foxp3(+)CD4(+)CD25(+)Treg数量的增加。因此，缺氧通过驱动 HIF-1 α 的表达来决定抗炎程序，HIF-1 α 的作用是增加天然存在的 CD4(+)CD25(+) Treg 的数量和抑制特性。
Recent data suggest that hypoxia and its principal molecular signature HIF-1 (hypoxia-inducing factor-1) may tune down inflammation by dictating anti-inflammatory programs. We tested the effects of hypoxia and HIF-1 alpha on the homeostasis of naturally occurring regulatory T cells (Treg) and their transcriptional activator Foxp3. Hypoxia induced a time-dependent increase in HIF-1 alpha in mouse and human T cells. Hypoxia upregulated the expression of Foxp3 in Jurkat T cells, human and murine mononuclear cells. The effects of hypoxia on Foxp3 expression were HIF-1 alpha-dependent as they were abolished upon transfection with short-interfering RNAs for HIF-1 alpha and promoted by HIF-1 alpha over-expression. Hypoxia increased the potency of Treg, as hypoxic CD4(+)CD25(+) lymphocytes were more effective than normoxic cells in suppressing the proliferation of CD4(+)CD25(-) effectors. In vivo expression of HIF-1 alpha achieved by hydrodynamic injection of the respective naked DNA similarly induced an increase in Foxp3 expression and an increase in the number of functionally active Foxp3(+)CD4(+)CD25(+) Treg. Thus, hypoxia dictates an anti-inflammatory program by driving expression of HIF-1 alpha that acts to increase the number and suppressive properties of naturally occurring CD4(+)CD25(+) Treg.