IL-4-induced arginase 1 suppresses alloreactive T cells in tumor-bearing mice
IL-4-induced arginase 1 suppresses alloreactive T cells in tumor-bearing mice
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DOI：
10.4049/jimmunol.170.1.270
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发表时间：
2003-01-01
影响因子：
4.4
通讯作者：
Zanovello, P
中科院分区：
文献类型：
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作者：
Bronte, V;Serafini, P;Zanovello, P
我们以前证明，一个专门的子集的未成熟的骨髓细胞迁移到淋巴器官作为肿瘤生长或免疫应激的结果，在那里他们抑制B和T细胞对抗原的反应。虽然需要NO抑制T细胞的有丝分裂原活化的骨髓抑制细胞（MSC），它是不需要抑制同种异体反应。在这项研究中，我们描述了一种新的机制，由MSC阻止T细胞增殖和CTL生成的同种异体抗原，这是由酶介导的精氨酸1（Arg 1）。我们发现，Arg 1增加超氧化物的产生在骨髓细胞通过一种途径，可能利用还原酶结构域的诱导型一氧化氮合酶（iNOS），和超氧化物是必需的Arg 1依赖性抑制T细胞功能。Arg 1在新鲜分离的MSC或克隆的MSC系中由IL-4诱导，因此被活化的Th 2细胞而不是Th 1细胞上调。相反，iNOS由IFN-γ和Th 1细胞诱导。由于Arg 1和iNOS共享L-精氨酸作为共同底物，我们的结果表明骨髓细胞中的L-精氨酸代谢是选择性干预逆转荷瘤宿主骨髓诱导功能障碍的潜在靶点。
We previously demonstrated that a specialized subset of immature myeloid cells migrate to lymphoid organs as a result of tumor growth or immune stress, where they suppress B and T cell responses to Ags. Although NO was required for suppression of mitogen activation of T cells by myeloid suppressor cells (MSC), it was not required for suppression of allogenic responses. In this study, we describe a novel mechanism used by MSC to block T cell proliferation and CTL generation in response to alloantigen, which is mediated by the enzyme arginase 1 (Arg1). We show that Arg1 increases superoxide production in myeloid cells through a pathway that likely utilizes the reductase domain of inducible NO synthase (iNOS), and that superoxide is required for Arg1-dependent suppression of T cell function. Arg1 is induced by IL-4 in freshly isolated MSC or cloned MSC lines, and is therefore up-regulated by activated Th2, but not Th1, cells. In contrast, iNOS is induced by IFN-gamma and Th1 cells. Because Arg1 and iNOS share L-arginine as a common substrate, our results indicate that L-arginine metabolism in myeloid cells is a potential target for selective intervention in reversing myeloid-induced dysfunction in tumor-bearing hosts.