Arginase‐1 is neither constitutively expressed in nor required for myeloid‐derived suppressor cell‐mediated inhibition of T‐cell proliferation,European Journal of Immunology

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Arginase‐1 is neither constitutively expressed in nor required for myeloid‐derived suppressor cell‐mediated inhibition of T‐cell proliferation
European Journal of Immunology ( IF 4.5 ) Pub Date : 2018-03-23 , DOI: 10.1002/eji.201747355
Zhen Bian ₁ , Ahmed Mansour Abdelaal ₁ , Lei Shi ₁ , Hongwei Liang ₁ , Lanqiao Xiong ₁ , Koby Kidder ₁ , Mahathi Venkataramani ₁ , Courtney Culpepper ₁ , Ke Zen ₂ , Yuan Liu ₁

Affiliation

Although previous reports suggest that tumor‐induced myeloid‐derived suppressor cells (MDSC) inhibit T cells by L‐arginine depletion through arginase‐1 activity, we herein show that arginase‐1 is neither inherently expressed in MDSC nor required for MDSC‐mediated inhibition. Employing Percoll density gradients, large expansions of MDSC in the bone marrow of tumor‐bearing mice were isolated and demonstrated potent inhibition in T‐cell proliferation activated by TCR‐ligation, Concanavalin A, PMA plus ionomycin, or IL‐2. Despite demonstrating characteristic immunosuppressive capacity, these MDSC exhibit no arginase‐1 expression and/or exert their inhibitory effects independent of arginase‐1 activity. However, arginase‐1 expression in MDSC can be induced by exposure to TCR‐activated T cells or their culture medium, but not T cells activated by other means or growing tumor cells. Further investigation reveals multiple cytokines secreted by TCR‐activated T cells as orchestrating two signaling‐relay axes, IL‐6‐to‐IL‐4 and GM‐CSF/IL‐4‐to‐IL‐10, leading to arginase‐1 expression in MDSC. Specifically, IL‐6 signaling increases IL‐4R, enabling IL‐4 to induce arginase‐1 expression; similarly, GM‐CSF in concert with IL‐4 induces IL‐10R, allowing IL‐10‐mediated induction. Surprisingly, our study indicates that induction of arginase‐1 expression is not conducive to the critical MDSC‐mediated inhibition toward T cells, which is rather dependent on direct cell contacts undiminished by PD‐L1 blockade or SIRPα deficiency.

中文翻译：

精氨酸酶1既不组成性表达，也不是髓样抑制细胞介导的T细胞增殖抑制所必需的

尽管以前的报道表明肿瘤诱导的髓样抑制细胞（MDSC）通过精氨酸酶-1的活性通过L-精氨酸的消耗来抑制T细胞，但我们在此表明，精氨酸酶-1既不是在MDSC中固有表达的，也不是MDSC介导的抑制作用所必需的。利用Percoll密度梯度，可以分离出荷瘤小鼠骨髓中MDSC的大量扩增，并显示出对TCR连接，伴刀豆球蛋白A，PMA加离子霉素或IL-2激活的T细胞增殖的有效抑制作用。尽管表现出特征性的免疫抑制能力，但这些MDSC仍不显示精氨酸酶-1的表达和/或发挥其抑制作用，而与精氨酸酶-1的活性无关。但是，暴露于TCR激活的T细胞或其培养基中可以诱导MDSC中精氨酸酶-1的表达，但不是通过其他方式激活的T细胞或正在生长的肿瘤细胞。进一步的研究表明，TCR激活的T细胞分泌的多种细胞因子协调着两个信号中继轴，即IL-6至IL-4和GM-CSF / IL-4至IL-10，从而导致精氨酸酶1的表达。在MDSC中。具体来说，IL-6信号传导增加IL-4R，使IL-4诱导精氨酸酶-1表达。同样，GM‐CSF与IL‐4共同诱导IL‐10R，允许IL‐10介导的诱导。出乎意料的是，我们的研究表明诱导精氨酸酶-1的表达不利于MDSC介导的对T细胞的关键抑制作用，而抑制作用主要取决于PD-L1阻断或SIRPα缺乏而不能减少的直接细胞接触。IL-6至IL-4和GM-CSF / IL-4至IL-10，导致MDSC中的精氨酸酶1表达。具体来说，IL-6信号传导增加IL-4R，使IL-4诱导精氨酸酶-1表达。同样，GM‐CSF与IL‐4共同诱导IL‐10R，允许IL‐10介导的诱导。出乎意料的是，我们的研究表明诱导精氨酸酶-1的表达不利于MDSC介导的对T细胞的关键抑制作用，而抑制作用主要取决于PD-L1阻断或SIRPα缺乏而不能减少的直接细胞接触。IL-6至IL-4和GM-CSF / IL-4至IL-10，导致MDSC中的精氨酸酶-1表达。具体来说，IL-6信号传导增加IL-4R，使IL-4诱导精氨酸酶-1表达。同样，GM‐CSF与IL‐4共同诱导IL‐10R，允许IL‐10介导的诱导。出乎意料的是，我们的研究表明诱导精氨酸酶-1的表达不利于MDSC介导的对T细胞的关键抑制作用，而抑制作用主要取决于PD-L1阻断或SIRPα缺乏而不能减少的直接细胞接触。

更新日期：2018-03-23

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