Department of Experimental Pediatrics, University Hospital, Health Campus Immunology, Infectiology and Inflammation, Otto-von-Guericke-University, Magdeburg 39120, Germany.
Department of Molecular Structural Biology, Helmholtz Centre for Infection Research, Braunschweig 38124, Germany.
Cell Death Differ. 2017 Oct;24(10):1739-1749. doi: 10.1038/cdd.2017.102. Epub 2017 Jun 23.
The blockade of inhibitory receptors such as CTLA-4 (CD152) is being used as immune-checkpoint therapy, offering a powerful strategy to restore effective immune responses against tumors. To determine signal components that are induced under the control of CTLA-4 we analyzed activated murine CD8 T cells by quantitative proteomics. Accurate mass spectrometry revealed that CTLA-4 engagement led to central changes in the phosphorylation of proteins involved in T-cell differentiation. Beside other targets, we discovered a CTLA-4-mediated induction of the translational inhibitor programmed cell death-4 (PDCD4) as a result of FoxO1 nuclear re-localization. PDCD4 further bound a distinct set of mRNAs including Glutaminase, which points out a critical role for CTLA-4 in CD8 T-cell metabolism. Consequently, PDCD4-deficient cytotoxic T-lymphocytes (CTLs) expressed increased amounts of otherwise repressed effector molecules and ultimately led to superior control of tumor growth in vivo. These findings reveal a novel CTLA-4-mediated pathway to attenuate CTLs and indicate the importance of post-transcriptional mechanisms in the regulation of anti-tumor immune responses.
阻断抑制性受体，如 CTLA-4（CD152），被用作免疫检查点疗法，提供了一种恢复针对肿瘤的有效免疫反应的强大策略。为了确定 CTLA-4 控制下诱导的信号成分，我们通过定量蛋白质组学分析了激活的小鼠 CD8 T 细胞。精确的质谱分析显示，CTLA-4 的结合导致参与 T 细胞分化的蛋白质磷酸化的核心变化。除了其他靶点外，我们还发现 CTLA-4 介导了翻译抑制剂程序性细胞死亡因子 4（PDCD4）的诱导，这是 FoxO1 核重新定位的结果。PDCD4 进一步结合了一组不同的 mRNA，包括谷氨酰胺酶，这表明 CTLA-4 在 CD8 T 细胞代谢中起着关键作用。因此，缺乏 PDCD4 的细胞毒性 T 淋巴细胞（CTL）表达了更多被抑制的效应分子，最终导致体内肿瘤生长的更好控制。这些发现揭示了一种新的 CTLA-4 介导的途径来减弱 CTL，并表明在调节抗肿瘤免疫反应中，转录后机制的重要性。
