College of Pharmacy, Division of Life and Pharmaceutical Sciences and Center for Cell Signaling & Drug Discovery Research, Ewha Womans University, Seoul, Korea.
Int J Cancer. 2010 Nov 1;127(9):2129-37. doi: 10.1002/ijc.25238.
T-box-containing protein expressed in T cells (T-bet) is a master transcription factor for the development of interferon (IFN) gamma-producing T helper 1 (Th1) cells and also functions in other immune cells including natural killer (NK), cytotoxic T lymphocytes and dendritic cells. T-bet-deficient mice increased susceptibility to viral infection and tumor development due to the defective functions of immune cells. T-bet is known to play a key role in NK-mediated antimetastatic response; however, it remains to be characterized whether T-bet is essential for in vivo tumor suppression mediated by T cells. Here, we have investigated in vivo tumor suppression effect of T-bet-restored T cells using T cell-specific and inducible T-bet transgenic mice generated in a T-bet-deficient background. T-bet-null mice increased susceptibility to tumor development, whereas induction of T cell-specific T-bet expression upon melanoma cell injection substantially suppressed tumor development by inducing IFNgamma production in T cells and tumor cell apoptosis. Late induction of T-bet expression in tumor-bearing mice produced comparable amounts of IFNgamma with control and significantly decreased tumor volume. In addition, increased melanoma lung metastasis in T-bet-deficient mice was strikingly inhibited by T-bet restoration in T cells. Intravenous injection of activated Th1 cells, not T-bet-null Th1 cells, attenuated metastatic melanoma progression, in addition, restoration of T-bet in T-bet-null Th1 cells certainly retrieved antimetastatic activity. These results suggest that T-bet expression in T cells is crucial for the control of tumor development and antimetastatic activity.
T 细胞中表达的 T 盒蛋白（T-bet）是干扰素（IFN）γ产生的辅助性 T 细胞 1（Th1）细胞发育的主要转录因子，也在包括自然杀伤（NK）、细胞毒性 T 淋巴细胞和树突状细胞在内的其他免疫细胞中发挥作用。由于免疫细胞功能缺陷，T-bet 缺陷小鼠易感染病毒和发生肿瘤。T-bet 已知在 NK 介导的抗肿瘤转移反应中发挥关键作用；然而，T-bet 是否对 T 细胞介导的体内肿瘤抑制至关重要仍有待确定。在这里，我们使用在 T-bet 缺陷背景下生成的 T 细胞特异性和诱导型 T-bet 转基因小鼠研究了 T-bet 恢复的 T 细胞的体内肿瘤抑制作用。T-bet 缺失小鼠易发生肿瘤发展，而在黑色素瘤细胞注射时诱导 T 细胞特异性 T-bet 表达可通过诱导 T 细胞产生 IFNγ和肿瘤细胞凋亡来显著抑制肿瘤发展。在荷瘤小鼠中晚期诱导 T-bet 表达可产生与对照相当数量的 IFNγ，并显著降低肿瘤体积。此外，T 细胞中 T-bet 的恢复显著抑制了 T-bet 缺陷小鼠的黑色素瘤肺转移。静脉注射激活的 Th1 细胞而非 T-bet 缺失的 Th1 细胞可抑制转移性黑色素瘤的进展，此外，T-bet 缺失的 Th1 细胞中 T-bet 的恢复确实恢复了抗肿瘤转移活性。这些结果表明，T 细胞中 T-bet 的表达对于控制肿瘤发生和抗肿瘤转移活性至关重要。
