Tumor-Educated CD11bhighIalow Regulatory Dendritic Cells Suppress T Cell Response through Arginase I
Tumor-Educated CD11bhighIalow Regulatory Dendritic Cells Suppress T Cell Response through Arginase I
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DOI：
10.4049/jimmunol.0803926
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发表时间：
2009-05-15
影响因子：
4.4
通讯作者：
Cao, Xuetao
中科院分区：
文献类型：
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作者：
Liu, Qiuyan;Zhang, Chaoxiong;Cao, Xuetao
肿瘤可以诱导肿瘤微环境中调节性T细胞等免疫抑制细胞的产生和积累，有助于肿瘤逃避免疫攻击。尽管基于树突状细胞（DC）的癌症疫苗可以启动抗肿瘤免疫反应，但参与耐受诱导的调节性DC亚群最近引起了广泛关注。我们之前的研究表明，脾、肺和肝的基质微环境可以编程产生具有调节功能的CD11c（低）CD11b（高）Ia（低）DC（CD11b（高）Ia（低）调节DC）。然而。肿瘤微环境是否以及如何能够编程生成或CD11b（高）Ia（低）调节性DC仍有待研究。在本研究中，我们使用新鲜分离的肿瘤细胞模拟肿瘤微环境来共培养树突状细胞，并发现新鲜分离的肿瘤细胞可以驱动树突状细胞分化为具有CD11c（低）Ib（高）la（低）表型和高表达IL-10、NO、血管内皮生长因子和精氨酸酶L的调节性树突状细胞。肿瘤教育的CD11b（高）Ia（低）调节性树突状细胞受到抑制CD4(+) T 细胞在体外和体内增殖。 3LL 肺癌衍生的 TGF-β 和 PGE(2) 负责生成或调节 DC。 PGE(2) 是调节性 DC 中的主要诱导剂或精氨酸酶 I。精氨酸酶 I 在抑制 3LL 肺癌诱导的调节性 DC 的 T 细胞反应中发挥了重要作用。在肿瘤组织中鉴定出 CD11b（高）Ia（低）DC 的天然对应物，从 3LL 肺癌组织中分选的 CD11b（高）Ia（低）DC 表达精氨酸酶 I 并抑制 T 细胞反应。因此，肿瘤可以教育DC分化为调节性DC亚群，从而有助于构建免疫抑制性肿瘤微环境，促进肿瘤免疫逃逸。免疫学杂志，2009，182：6207-6216。
Tumors can induce generation and accumulation of the immunosuppressive cells such as regulatory T cells in the tumor microenvironment, contributing to tumor escape from immunological attack. Although dendritic cell (DC)-based cancer vaccine can initiate antitumor immune response, regulatory DC subsets involved in the tolerance induction attracted much attention recently. Our previous studies demonstrate that the stromal microenvironment of the spleen, lung, and liver can program generation of CD11c(low)CD11b(high)Ia(low) DCs with regulatory function (CD11b(high)Ia(low) regulatory DCs). However. whether and how the tumor microenvironment can program generation or CD11b(high)Ia(low) regulatory DCs remain to be investigated. In this study, we used the freshly isolated tumor cells to mimic tumor microenvironment to coculture DCs and round that the freshly isolated tumor cells could drive DCs to differentiate into regulatory DCs with a CD11c(low)Ib(high)la(low) phenotype and high expression or IL-10, NO, vascular endothelial growth factor, and arginase L. Tumor-educated CD11b(high)Ia(low) regulatory DCs inhibited CD4(+) T cell proliferation both in vitro and in vivo. 3LL lung cancer-derived TGF-beta and PGE(2) were responsible for the generation or regulatory DCs. PGE(2) was the main inducer or arginase I in regulatory DCs. Arginase I played a major role in the suppression of T cell response by regulatory DCs induced by 3LL lung cancer. A natural counterpart of CD11b(high)Ia(low) DCs was identified in tumor tissue, and CD11b(high)Ia(low) DCs sorted from 3LL lung cancer tissue expressed arginase I and inhibited T cell response. Therefore, tumors can educate DCs to differentiate into a regulatory DC subset, which contributes to constitution of the immunosuppressive tumor microenvironment and promotes tumor immune escape. The Journal of Immunology, 2009, 182: 6207-6216.