Up-regulated expression of indoleamine 2,3-dioxygenase 1 in non-Hodgkin lymphoma correlates with increased regulatory T-cell infiltration
Up-regulated expression of indoleamine 2,3-dioxygenase 1 in non-Hodgkin lymphoma correlates with increased regulatory T-cell infiltration
复制标题
非霍奇金淋巴瘤中吲哚胺 2,3-双加氧酶 1 表达上调与调节性 T 细胞浸润增加相关
DOI：
10.3109/10428194.2013.804917
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发表时间：
2014-02-01
影响因子：
2.6
通讯作者：
Wang, Xin
中科院分区：
文献类型：
--
作者：
Liu, Xiao-Qian;Lu, Kang;Wang, Xin
摘要吲哚胺2，3-双加氧酶1(IDO1)是色氨酸代谢的关键酶，表达于正常细胞和肿瘤细胞的某些亚群，参与肿瘤诱导的耐受。然而，其中涉及的机制尚不清楚。一种假说认为IDO1可能参与调节性T细胞(Tregs)的增殖和转化。在本研究中，我们检测了非霍奇金淋巴瘤(NHL)组织中IDO1和叉头盒P3(FoxP3)的水平，并进行了体外实验，以探讨IDO1在非霍奇金淋巴瘤T细胞耐受中的作用。结果表明，IDO1mRNA和蛋白在NHL组织中的表达明显高于反应性增生的淋巴结组织。IDO1表达上调与临床分期较晚、肿瘤体积较大、血清乳酸脱氢酶(LDH)较高有关，提示预后较差。随着IDO1水平的升高，Foxp3mRNA和蛋白水平显著升高。小鼠CD_4+CD_(25)−T细胞与A_(20)细胞共培养后，可启动CD_4+CD_(25+)T细胞的转化，对混合淋巴细胞反应具有抑制作用。此外，IDO 1的有效抑制剂1-甲基-L-色氨酸可减弱CD_4+CD_(25)−T细胞向CD_4+CD_(25)+FoxP3+T细胞的转化。结果提示，非霍奇金淋巴瘤组织中IDO_1的上调可能通过促进肿瘤微环境中CD_4+CD_(25)−T细胞向CD_4+CD_(25)+FoxP_3+T细胞的转化，促进FoxP_3+Treg细胞的发育和侵袭，从而诱导局部免疫耐受。这可能是NHL逃避免疫控制的一种新机制。
Abstract Indoleamine 2,3-dioxygenase 1 (IDO1), which is a key enzyme in tryptophan metabolism expressed in some subsets of normal and neoplastic cells, participates in tumor-induced tolerance. However, the mechanisms involved are not clearly understood. A hypothesis suggests that IDO1 may be involved in proliferation and conversion of regulatory T cells (Tregs). In this study, we evaluated the levels of IDO1 and forkhead box P3 (FoxP3) in non-Hodgkin lymphoma (NHL) tissues and performed ex vivo experiments to investigate the role of IDO1 on T-cell tolerance in NHL. The results showed that expressions of IDO1 mRNA and protein were coincidentally higher in NHL tissues than in reactive hyperplasia of lymph node tissues. Up-regulation of IDO1 was correlated with later clinical phases, larger tumors and higher serum lactate dehydrogenase (LDH), and indicated a worse prognosis. FoxP3 mRNA and protein levels were markedly increased alongside elevated IDO1 levels. Co-culture of murine CD4 + CD25− T cells with A20 cells could initiate the conversion of CD4 + CD25+ T cells, which showed a suppressive function in the mixed lymphocyte reaction. Moreover, the potent inhibitor of IDO1, 1-methyl-l-tryptophan, attenuated the conversion of CD4 + CD25− T cells into CD4 + CD25+ FoxP3 + T cells. The results suggested that up-regulation of IDO1 in NHL tissues could induce local immune tolerance by favoring development and infiltration of FoxP3 + Tregs through the conversion of CD4 + CD25− T cells into CD4 + CD25+ FoxP3 + T cells in the tumor microenvironment. This could be a novel mechanism of NHL escape from immune control.