T-Cell Activation under Hypoxic Conditions Enhances IFN-γ Secretion
T-Cell Activation under Hypoxic Conditions Enhances IFN-γ Secretion
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DOI：
10.1165/rcmb.2008-0139oc
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发表时间：
2010-01-01
影响因子：
6.4
通讯作者：
Georas, Steve N.
中科院分区：
文献类型：
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作者：
Roman, Jessica;Rangasamy, Tirumalai;Georas, Steve N.
二级淋巴器官和外周组织在稳定状态和炎症期间都以缺氧微环境为特征。虽然缺氧调节t细胞的代谢和存活，但我们对缺氧是否或如何影响t细胞活化知之甚少。在常氧（20% O-2）和缺氧（11% O-2）条件下，我们用抗体直接刺激小鼠CD4(+) T细胞。在这里，我们报告了缺氧条件下的刺激增加了效应CD4(+) t细胞因子的分泌，特别是ifn - γ。缺氧对ifn - γ分泌的增强作用与小鼠品系无关，并且在缺乏缺氧诱导因子-lot基因拷贝的小鼠CD4(+) T细胞中也不受影响。利用ifn - γ受体缺陷小鼠的T细胞和瞬时转染Jurkat T细胞的启动子报告子研究，我们发现缺氧对ifn - γ表达的增强作用不是由于对ifn - γ消耗或近端启动子活性的影响。相反，核红细胞2 p45相关因子2的缺失减弱了缺氧对ifn - γ分泌和其他细胞因子的增强作用。我们得出结论，缺氧是CD4(+) T细胞中效应细胞因子分泌的一种先前未被充分认识的调节剂。
Secondary lymphoid organs and peripheral tissues are characterized by hypoxic microenvironments, both in the steady state and during inflammation. Although hypoxia regulates T-cell metabolism and survival, very little is known about whether or how hypoxia influences T-cell activation. We stimulated mouse CD4(+) T cells in vitro with antibodies directed against the T-cell receptor (CD3) and CD28 under normoxic (20% O-2) and hypoxic (11% O-2) conditions. Here we report that stimulation under hypoxic conditions augments the secretion of effector CD4(+) T-cell cytokines, especially IFN-gamma. The enhancing effects of hypoxia on IFN-gamma secretion were independent of mouse strain, and were also unaffected using CD4(+) T cells from mice lacking one copy of the gene encoding hypoxia-inducible factor-lot. Using T cells from IFN-gamma receptor-deficient mice and promoter reporter studies in transiently transfected Jurkat T cells, we found that the enhancing effects of hypoxia on IFN-gamma expression were not due to effects on IFN-gamma consumption or proximal promoter activity. In contrast, deletion of the transcription factor, nuclear erythrold 2 p45-related factor 2 attenuated the enhancing effect of hypoxia on IFN-gamma secretion and other cytokines. We conclude that hypoxia is a previously underappreciated modulator of effector cytokine secretion in CD4(+) T cells.