Bronte Vincenzo, Serafini Paolo, De Santo Carmela, Marigo Ilaria, Tosello Valeria, Mazzoni Alessandra, Segal David M, Staib Caroline, Lowel Marianne, Sutter Gerd, Colombo Mario P, Zanovello Paola
Department of Oncology and Surgical Sciences, University of Padua, Padua, Italy.
J Immunol. 2003 Jan 1;170(1):270-8. doi: 10.4049/jimmunol.170.1.270.
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.
我们先前证明，由于肿瘤生长或免疫应激，未成熟髓样细胞的一个特定亚群会迁移至淋巴器官，在那里它们会抑制B细胞和T细胞对抗原的反应。虽然髓样抑制细胞（MSC）抑制T细胞丝裂原激活需要一氧化氮（NO），但抑制同种异体反应则不需要。在本研究中，我们描述了MSC用于阻断T细胞增殖和针对同种异体抗原产生细胞毒性T淋巴细胞（CTL）的一种新机制，该机制由精氨酸酶1（Arg1）介导。我们发现，Arg1通过一条可能利用诱导型一氧化氮合酶（iNOS）还原酶结构域的途径增加髓样细胞中的超氧化物生成，并且超氧化物是Arg1依赖性抑制T细胞功能所必需的。Arg1在新鲜分离的MSC或克隆的MSC系中由白细胞介素-4（IL-4）诱导，因此由活化的辅助性T细胞2（Th2）而非辅助性T细胞1（Th1）上调。相反，iNOS由干扰素-γ（IFN-γ）和Th1细胞诱导。由于Arg1和iNOS共享L-精氨酸作为共同底物，我们的结果表明，髓样细胞中的L-精氨酸代谢是选择性干预以逆转荷瘤宿主中髓样细胞诱导的功能障碍的一个潜在靶点。
