Bollinger Thomas, Gies Sydney, Naujoks Julius, Feldhoff Lea, Bollinger Annalena, Solbach Werner, Rupp Jan
Department of Molecular Biology, University of Geneva, Switzerland; Institute of Medical Microbiology and Hygiene, University of Lübeck, Germany;
Institute of Medical Microbiology and Hygiene, University of Lübeck, Germany;
J Leukoc Biol. 2014 Aug;96(2):305-12. doi: 10.1189/jlb.3A0813-426RR. Epub 2014 Mar 24.
The central oxygen sensitive transcription factor HIF-1α has been implicated in the differentiation of n(T(reg)) and Th17 cells and to orchestrate metabolic changes of activated T cells. However, data on the functional relevance of HIF-1α and Hox, in general, for nT(reg)-suppressive activity and T cell function in primary human cells are still missing. Therefore, we analyzed the effect of Hox and HIF-1α on human T(res), n(Treg), and Th17 cells. Under Hox, nT(reg)-mediated suppression of T(res) proliferation, CD25 expression, and secretion of IFN-γ were significantly reduced, whereas expression levels of VEGF, TNF-α, and IL-10 were significantly increased. In contrast to observations in mice, Th17 lineage commitment, as determined by RORγt expression, was not affected by activation or inhibition of HIF-1α expression using DMOG or YC-1 treatment, respectively. Nevertheless, the secretion of IL-17A was increased by DMOG and reduced by YC-1 under Th17-skewing conditions in a dose- dependent manner. In conclusion, Hox and HIF-1α substantially influence human T cell-mediated immune responses by modulation of nT(reg)-suppressive function and IL-17A secretion by Th17 cells.
核心氧敏感转录因子HIF-1α与n(T(reg))和Th17细胞的分化有关，并协调活化T细胞的代谢变化。然而，关于HIF-1α和Hox一般对原代人细胞中nT(reg)抑制活性和T细胞功能的功能相关性的数据仍然缺失。因此，我们分析了Hox和HIF-1α对人T(res)、n(Treg)和Th17细胞的影响。在Hox作用下，nT(reg)介导的对T(res)增殖、CD25表达和IFN-γ分泌的抑制作用显著降低，而VEGF、TNF-α和IL-10的表达水平显著升高。与在小鼠中的观察结果不同，分别使用DMOG或YC-1处理激活或抑制HIF-1α表达，由RORγt表达确定的Th17谱系定向不受影响。然而，在Th17偏向条件下，DMOG可使IL-17A分泌增加，YC-1可使其分泌减少，且呈剂量依赖性。总之，Hox和HIF-1α通过调节nT(reg)抑制功能和Th17细胞的IL-17A分泌，对人T细胞介导的免疫反应有实质性影响。
