Critical role of OX40 in the expansion and survival of CD4 T-cell-derived double-negative T cells.
Critical role of OX40 in the expansion and survival of CD4 T-cell-derived double-negative T cells.
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OX40 在 CD4 T 细胞衍生的双阴性 T 细胞的扩增和存活中的关键作用
DOI：
10.1038/s41419-018-0659-x
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发表时间：
2018-05-23
影响因子：
9
通讯作者：
Zhang D
中科院分区：
文献类型：
--
作者：
Sun G;Sun X;Li W;Liu K;Tian D;Dong Y;Sun X;Xu H;Zhang D
CD 4 + T细胞转化的CD 4 − CD 8 −双阴性（cDNT）在维持免疫耐受方面具有很强的抑制活性，而IL-2促进cDNT增殖并增强cDNT对凋亡的抵抗。然而，调节cDNT存活的内在机制仍然未知。在这里，我们证明了OX 40分子在cDNT上高度表达。OX 40的表达在体内外促进cDNT增殖和抑制cDNT凋亡中是必需的。OX 40通过调节Bcl-2、Bcl-xL、Survivin和BCL 2L 11的表达促进cDNT的存活。经典NF-κB细胞信号在通过cDNT中的OX 40传递必需的分裂和存活信号中起重要作用。IL-2通过上调OX 40分子的表达促进cDNT的存活。IL-2通过下调PPARα表达促进OX 40表达。总之，我们阐明了OX 40是调节cDNT增殖和存活的关键分子。IL-2通过下调PPARα与OX 40启动子的结合，促进OX 40表达，进而上调Bcl-2、Bcl-xL和Survivin的表达，最终促进cDNT的增殖，抑制其凋亡。
CD4+ T-cell-converted CD4−CD8− double negative (cDNT) have strong suppressive activity in the maintenance of immune tolerance, whereas IL-2 promotes cDNT proliferation and enhances cDNT resistance to apoptosis. However, the intrinsic mechanisms that regulate the survival of cDNT are still unknown. Here we demonstrate that the OX40 molecule was highly expressed on cDNT. The expression of OX40 was necessary to promote proliferation and inhibit apoptosis of cDNT in vivo and in vitro. OX40 promoted the survival of cDNT by regulating the expression of Bcl-2, Bcl-xL, Survivin, and BCL2L11. Canonical NF-κB cell signaling played an important role in the transmission of essential division and survival signals through OX40 in cDNT. IL-2 promoted the survival of cDNT in part via elevating the expression of the OX40 molecule. IL-2 promoted OX40 expression via downregulating the PPARα expression. In conclusion, we elucidated that OX40 is a key molecule that regulates cDNT proliferation and survival. IL-2 promoted OX40 expression by downregulating the PPARα binding to the OX40 promoter, leading to the elevated expression of Bcl-2, Bcl-xL, and Survivin in cDNT, which finally resulted in the promoted proliferation and decreased apoptosis of cDNT.
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