Physiological function of phospholipase D2 in anti-tumor immunity: regulation of CD8(+) T lymphocyte proliferation.
Physiological function of phospholipase D2 in anti-tumor immunity: regulation of CD8(+) T lymphocyte proliferation.
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DOI：
10.1038/s41598-018-24512-x
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发表时间：
2018-04-19
影响因子：
4.6
通讯作者：
Kanaho Y
中科院分区：
文献类型：
--
作者：
Ngo Thai Bich V;Hongu T;Miura Y;Katagiri N;Ohbayashi N;Yamashita-Kanemaru Y;Shibuya A;Funakoshi Y;Kanaho Y
哺乳动物中两种主要的磷脂酶D （PLD1和PLD2）同工酶将膜磷脂磷脂酰胆碱水解为胆碱和脂质信使磷脂酸。虽然它们在癌细胞中的作用已经得到了很好的研究，但它们在肿瘤微环境中的功能尚未明确。在这里，我们证明了细胞毒性CD8+ T细胞中的PLD2通过调节细胞增殖在抗肿瘤免疫中起着至关重要的作用。我们发现，pld2敲除小鼠皮下移植癌细胞形成的肿瘤生长增强。有趣的是，这种表型被发现至少部分归因于骨髓细胞中Pld2的消融。在pld2敲除小鼠产生的肿瘤中，诱导癌细胞死亡的CD8+ T细胞数量显著减少。此外，CD3/ cd28刺激的原代培养脾CD8+ T细胞的增殖被Pld2消融明显抑制。最后，CD3/ cd28依赖性的Erk1/2和Ras的激活在pld2缺失的CD8+ T细胞中被抑制。综上所述，这些结果表明，CD8+ T细胞中的PLD2通过激活Ras/Erk信号通路，在其增殖中发挥关键作用，从而调节抗肿瘤免疫。
Two major phospholipase D (PLD) isozymes in mammals, PLD1 and PLD2, hydrolyze the membrane phospholipid phosphatidylcholine to choline and the lipid messenger phosphatidic acid. Although their roles in cancer cells have been well studied, their functions in tumor microenvironment have not yet been clarified. Here, we demonstrate that PLD2 in cytotoxic CD8+ T cells plays a crucial role in anti-tumor immunity by regulating their cell proliferation. We found that growth of tumors formed by subcutaneously transplanted cancer cells is enhanced in Pld2-knockout mice. Interestingly, this phenotype was found to be at least in part attributable to the ablation of Pld2 from bone marrow cells. The number of CD8+ T cells, which induce cancer cell death, significantly decreased in the tumor produced in Pld2-knockout mice. In addition, CD3/CD28-stimulated proliferation of primary cultured splenic CD8+ T cells is markedly suppressed by Pld2 ablation. Finally, CD3/CD28-dependent activation of Erk1/2 and Ras is inhibited in Pld2-deleted CD8+ T cells. Collectively, these results indicate that PLD2 in CD8+ T cells plays a key role in their proliferation through activation of the Ras/Erk signaling pathway, thereby regulating anti-tumor immunity.
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