Polyamines polarized Th2/Th9 cell-fate decision by regulating GATA3 expression
Polyamines polarized Th2/Th9 cell-fate decision by regulating GATA3 expression
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多胺通过调节 GATA3 表达来极化 Th2/Th9 细胞的命运决定
DOI：
10.1016/j.abb.2020.108587
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发表时间：
2020
影响因子：
3.9
通讯作者：
Koji Hase
中科院分区：
文献类型：
--
作者：
Atsuo Nakamura;Daisuke Takahashi*;Yutaka Nakamura;Takahiro Yamada;Mitsuharu Matsumoto* (*equal correspondence);Koji Hase
原核生物和真核生物产生的多胺都是具有多效性的生物活性物质。越来越多的证据表明，多胺通过抑制单核细胞和巨噬细胞中促炎症细胞因子的表达而参与抗炎反应。然而，多胺对CD4+T细胞反应的影响仍有待阐明。在这里，我们研究了多胺在体外对幼稚的CD4+T细胞命运决定的影响。我们发现内源性多胺对辅助性T细胞2(Th2)的发育是必不可少的。多胺生物合成抑制剂DL-2-二氟甲基鸟氨酸(DFMO)处理后，在Th2偏斜的条件下，CD4+T细胞中GATA3的表达减少。外源性多胺的补充挽救了DFMO治疗引起的CD4+T细胞GATA3下调。转录组分析显示，即使在Th2偏斜的情况下，内源性多胺的剥夺也会导致Th9相关基因如IL9、IRF4和BATF3的上调。在Th2和Th9偏斜的情况下，细胞内多胺的耗尽减少了GATA3的表达，但增加了产生IL-9的CD4+T细胞。此外，口服DFMO可增加小鼠小肠中产生IL-9的CD4+T细胞。因此，我们的数据表明，多胺在Th2/Th9平衡的调节中起着关键作用。
Polyamines produced by both prokaryotes and eukaryotes are bioactive substances with pleiotropic effects. Accumulating evidence has demonstrated that polyamines contribute to anti-inflammatory responses by suppressing the expression of proinflammatory cytokines in mononuclear cells and macrophages. However, the effects of polyamines on CD4+T cell responses remain to be elucidated. Here, we investigated the effect of polyamines on cell fate decisions of naïve CD4+T cellsin vitro. We found that endogenously generated polyamines are essential for the development of T helper 2 (Th2) cells. Treatment with DL-2-difluoromethylornithine (DFMO), an inhibitor of polyamine biosynthesis, diminished GATA3 expression in CD4+T cells under Th2-skewed conditions. Supplementation of exogenous polyamines rescued GATA3 downregulation caused by DFMO treatment in CD4+T cells. Transcriptome analysis revealed that deprivation of endogenous polyamines resulted in upregulated Th9-related genes, such asIl9,Irf4, andBatf3, even under the Th2-skewing conditions. Depletion of intracellular polyamines reduced GATA3 expression but increased IL-9-producing CD4+T cells under both Th2 and Th9-skewing conditions. Furthermore, oral administration of DFMO increased IL-9-producing CD4+T cells in small intestine in mice. Thus, our data indicate that polyamines play a critical role in the regulation of the Th2/Th9 balance.