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Down-Regulation and Apoptosis of T Cells through Oxygen-Dependent Pathways1
,
* State Key Laboratory of Biocontrol,
State Key Laboratory of Oncology in Southern China,
Department of Pathology, Cancer Center, and
Department of Immunology, Sun Yat-Sen University, Guangzhou, People’s Republic of China
Defects in the CD3/TCR complex and impairment of T cell function are necessary for tumor evasion, but the underlying mechanisms are incompletely understood. We found that culture supernatants from several types of solid tumor cell lines drove human monocytes to become tolerogenic semimature dendritic cells (TDCs). Upon encountering T cells, the TDCs triggered rapid down-regulation of CD3
and TCR-
/β and subsequent apoptosis in autologous T cells. Consistent with these results, accumulation of immunosuppressive DCs coincided with CD3 down-regulation and T cell deletion in cancer nests of human tumors. The impaired T cell function was mediated by factor(s) released by live TDCs after direct interaction with lymphocytes. Also, the TDC-induced effect on T cells was markedly reduced by blocking of NADPH oxidase but not by inhibition of arginase, inducible NO synthase (iNOS), IDO, or IFN-
. Moreover, we found that hyaluronan fragments constituted a common factor produced by a variety of human tumor cell lines to induce formation of TDCs. These observations indicate that tumor microenvironments, including hyaluronan fragments derived from cancer cells, educate DCs to adopt a semimature phenotype, which in turn aids tumor immune escape by causing defects in the CD3/TCR complex and deletion of T cells.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by the Outstanding Young Scientist Fund and project grants from the National Natural Science Foundation of China (30425025, 30672388 and 30730086), the "973" Program (2004CB518801 and 2007CB512404), and the Natural Science Foundation of Guangdong (05200303).
2 Address correspondence and reprint requests to Dr. Limin Zheng, College of Life Sciences, Sun Yat-Sen University, Guangzhou 510 275, People’s Republic of China. E-mail address: zhenglm{at}mail.sysu.edu.cn or Dr. Changyou Wu, Department of Immunology, Zhongshan Medical School, Sun Yat-Sen University, Guangzhou 510 089, People’s Republic of China. E-mail address: changyou_wu{at}yahoo.com
3 Abbreviations used in this paper: DC, dentritic cell; TSN, tumor culture supernatant; TDC, TSN-exposed tolerogenic semimature DC; iNOS, inducible nitric oxide synthase; iDC, immature DC; mDC, mature DC; ROS, reactive oxygen species; HA, hyaluronan; DPI, diphenyleneiodonium; SOD, superoxide dismutase; 1-MT, 1-methyl-tryptophan.
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