Hormonal vitamin D up-regulates tissue-specific PD-L1 and PD-L2 surface glycoprotein expression in humans but not mice
Hormonal vitamin D up-regulates tissue-specific PD-L1 and PD-L2 surface glycoprotein expression in humans but not mice
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DOI：
10.1074/jbc.m117.793885
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发表时间：
2017-12-15
影响因子：
4.8
通讯作者：
White, John H.
中科院分区：
文献类型：
--
作者：
Dimitrov, Vassil;Bouttier, Manuella;White, John H.
PD-L1(程序性死亡配体1)和PD-L2是细胞表面糖蛋白，与T细胞上的程序性死亡1(PD-1)相互作用以减轻炎症。PD-1信号通路因其在抑制抗肿瘤免疫的病理生理学背景下的作用而引起了人们的浓厚兴趣。同样，维生素D信号也因其在刺激天然免疫和抑制炎症反应方面的非经典作用而受到越来越多的研究。在这里，我们证明了荷尔蒙1，25-二羟基维生素D(1，25D)是通过维生素D受体(一种配体调节的转录因子)直接转录诱导编码PD-L1和PD-L2的人类基因。1，25D刺激上皮细胞和髓系细胞中PD-L1编码基因的转录，而编码更具组织限制性的PD-L2基因仅在髓系细胞中调节。我们鉴定并鉴定了位于这两个基因中的维生素D反应元件(VDRE)，结果表明，1，25D处理可诱导上皮细胞和髓系细胞中PD-L1在细胞表面的表达。在与原代人类T细胞的共培养实验中，经1，25D处理的上皮细胞抑制了CD4(+)和CD8(+)细胞的激活，并抑制了炎性细胞因子的产生，这种抑制方式被抗PD-L1封闭抗体所消除。与之前观察到的维生素D对免疫的物种特异性调节一致，VDRE存在于灵长类基因中，但在小鼠中既不存在VDRE，也不存在1，25D的调节。这些发现加强了1，25D在控制炎症免疫反应中的生理作用，但可能是一把双刃剑，因为它们表明人类体内维生素D信号的升高可能会抑制抗肿瘤免疫。
PD-L1 (programmed death ligand 1) and PD-L2 are cell-surface glycoproteins that interact with programmed death 1 (PD-1) on T cells to attenuate inflammation. PD-1 signaling has attracted intense interest for its role in a pathophysiological context: suppression of anti-tumor immunity. Similarly, vitamin D signaling has been increasingly investigated for its non-classical actions in stimulation of innate immunity and suppression of inflammatory responses. Here, we show that hormonal 1,25-dihydroxyvitamin D (1,25D) is a direct transcriptional inducer of the human genes encoding PD-L1 and PD-L2 through the vitamin D receptor, a ligand-regulated transcription factor. 1,25D stimulated transcription of the gene encoding PD-L1 in epithelial and myeloid cells, whereas the gene encoding the more tissue-restricted PD-L2 was regulated only in myeloid cells. We identified and characterized vitamin D response elements (VDREs) located in both genes and showed that 1,25D treatment induces cell-surface expression of PD-L1 in epithelial and myeloid cells. In co-culture experiments with primary human T cells, epithelial cells pretreated with 1,25D suppressed activation of CD4(+) and CD8(+) cells and inhibited inflammatory cytokine production in a manner that was abrogated by anti-PD-L1 blocking antibody. Consistent with previous observations of species-specific regulation of immunity by vitamin D, the VDREs are present in primate genes, but neither the VDREs nor the regulation by 1,25D is present in mice. These findings reinforce the physiological role of 1,25D in controlling inflammatory immune responses but may represent a double-edged sword, as they suggest that elevated vitamin D signaling in humans could suppress anti-tumor immunity.