The TGF-b/SOX4 axis and ROS-driven autophagy co-mediate CD39 expression in regulatory T-cells
The TGF-b/SOX4 axis and ROS-driven autophagy co-mediate CD39 expression in regulatory T-cells
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DOI：
10.1096/fj.201902664
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发表时间：
2020-04-22
期刊：
影响因子：
4.8
通讯作者：
Schmetterer, Klaus G.
中科院分区：
文献类型：
--
作者：
Gerner, Marlene C.;Ziegler, Liesa S.;Schmetterer, Klaus G.
人调节性T细胞（Treg）上的外核苷酸酶CD 39是一种重要的免疫调节因子，其在自身免疫性疾病和癌症免疫抑制中失调。我们在这里定义了Treg上的CD 39表达不依赖于Treg特异性转录因子FOXP 3和HELIOS，并且由典型的TGF-β和mTOR信号传导促进。此外，TGF-β介导的CD 39上调被活性氧（ROS）驱动的自噬抵消。与此同时，CD 39（+）外周血Treg构成了一个独特的谱系，具有低自噬通量和缺乏ROS产生。具有罕见自噬遗传缺陷的患者显示出超生理水平的CD 39（+）Treg，验证了我们在体内的观察结果。这些生物学过程依赖于不同的转录程序，其中CD 39（+）Treg表达低水平的两个基因，NEFL和PLAC 8，这两个基因被认为参与自噬。此外，TGF-β下游转录因子SOX 4在CD 39（+）Treg中选择性上调。Treg中S 0X 4的过表达强烈增加了⑶ 39表达，而Crispr/Cas9介导的Treg中S 0X 4的敲除具有相反的效果。因此，我们确定了SOX 4在免疫调节中的关键作用，并提供了涉及Treg中致耐受性线索和自噬相互作用的新见解。
The ectonucleotidase CD39 on human regulatory T-cells (Treg) is an important immune regulator which is dysregulated in autoimmune diseases and cancer immunosuppression. We here define that CD39 expression on Treg is independent of the Treg-specific transcription factors FOXP3 and HELIOS and promoted by canonical TGF-b- and mTOR-signaling. Furthermore, the TGF-b mediated upregulation of CD39 is counteracted by reactive oxygen species (ROS)-driven autophagy. In line, CD39(+) peripheral blood Treg constitute a distinct lineage with low autophagic flux and absent ROS production. Patients with rare genetic defects in autophagy show supraphysiological levels of CD39(+) Treg, validating our observations in vivo. These biological processes rely on a distinct transcriptional program with CD39(+) Treg expressing low levels of two genes with putative involvement in autophagy, NEFL and PLAC8. Furthermore, the TGF-b downstream transcription factor SOX4 is selectively upregulated in CD39(+) Treg. Overexpression of SOX4 in Treg strongly increases CD39 expression, while Crispr/Cas9-mediated knockout of SOX4 in Treg has the opposing effect. Thus, we identify a crucial role of SOX4 in immune regulation and provide new insights involving the interplay of tolerogenic cues and autophagy in Treg.