Tumor-specific cytotoxic T cell generation and dendritic cell function are differentially regulated by interleukin 27 during development of anti-tumor immunity
Tumor-specific cytotoxic T cell generation and dendritic cell function are differentially regulated by interleukin 27 during development of anti-tumor immunity
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DOI：
10.1002/ijc.24107
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发表时间：
2009-03-15
影响因子：
6.4
通讯作者：
Yoshida, Hiroki
中科院分区：
文献类型：
--
作者：
Shinozaki, Yukari;Wang, Sen;Yoshida, Hiroki
白介素27(IL-27)是IL-12细胞因子家族的一员，具有促进Th1细胞增殖和抗炎的作用。IL-27可促进肿瘤特异性细胞毒性T淋巴细胞(CTL)的诱导，以对抗多种肿瘤。然而，IL-27抑制淋巴细胞细胞因子的产生和树突状细胞(DC)的抗原提呈功能。为了研究IL-27在体内抗肿瘤免疫中的作用，我们用WSX-1(IL-27受体阿尔法链)缺陷(WSX-1(-/-))小鼠检测了IL-27介导的抗肿瘤效应。在接种B16黑色素瘤细胞的WSX-1(-/-)小鼠中，肿瘤生长速度高于野生型(WT)小鼠。因此，WSX-1(-/-)小鼠的肿瘤特异性CTL生成低于WT小鼠。WSX-1(-/-)小鼠的CTL诱导不能通过转移Trp2多肽冲击的WT DC来恢复，这表明IL-27是产生肿瘤特异性CTL所直接需要的。然而，将Trp2多肽冲击的WSX-1(-/-)DC转移到荷瘤小鼠体内，在抑制肿瘤生长和产生CTL方面比WT DC更有效，表明IL-27对DC功能有抑制作用。最后，WT CD8(+)T细胞和KO DC的组合在产生抗原特异性CTL方面比任何其他组合更有效。WT CD8(+)T细胞与WSX-1(-/-)DC联合培养后，穿孔素基因表达和肿瘤特异性CD8(+)T细胞百分率也最高。提示IL-27在肿瘤免疫生成过程中促进CTL生成，同时抑制DC功能。WT T细胞和IL-27信号缺陷树突状细胞的结合可能具有治疗肿瘤的潜力。(C)2008年Wiley-Liss，Inc.
Interleukin (IL-) 27 is a member of IL-12 cytokine family with Th1-promoting and anti-inflammatory effects. IL-27 has' been shown to facilitate tumor-specific cytotoxic T lymphocyte (CTL) induction against various tumors. However, IL-27 suppresses cytokine production of lymphocytes and antigen-presenting function of dendritic cells (DCs). To examine the in vivo role of IL-27 in generation of anti-tumor immunity, we examined IL-27-mediated antitumor-effects using WSX-1 (IL-27 receptor alpha chain)-deficient (WSX-1(-/-)) mice. In WSX-1(-/-) mice inoculated with B16 melanoma cells, tumor growth was higher than in wild-type (WT) mice. Accordingly, tumor-specific CTL generation was lower in WSX-1(-/-) mice than in WT mice. CTL induction in WSX-1(-/-) mice was not restored by transfer of WT DCs pulsed with TRP2 peptide, indicating that IL-27 is directly required for generation of tumor-specific CTLs. However, when transferred into tumor-bearing mice, WSX-1(-/-) DCs pulsed with TRP2 peptide was more potent than WT DCs in tumor growth inhibition and generation of CTLs, indicating suppressive effects of IL-27 on DC function. Finally, the combination of WT CD8(+) T cells and KO DCs is more potent in generation of antigen-specific CTLs than any other combinations. Expression of perforin gene and percentages of tumor-specific CD8(+) T cells were also the highest in the combination of WT CD8(+) T cells and WSX-1(-/-) DCs. It was thus revealed that IL-27 promotes CTL generation while suppressing DC function during generation of tumor immunity. The combination of WT T cells and IL-27 signal-defective DCs may have therapeutic potential against tumors. (c) 2008 Wiley-Liss, Inc.