Programmed death-1 controls T cell survival by regulating oxidative metabolism.
Programmed death-1 controls T cell survival by regulating oxidative metabolism.
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DOI：
10.4049/jimmunol.1402180
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发表时间：
2015-06-15
期刊：
影响因子：
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通讯作者：
Byersdorfer CA
中科院分区：
文献类型：
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作者：
Tkachev V;Goodell S;Opipari AW;Hao LY;Franchi L;Glick GD;Ferrara JL;Byersdorfer CA
共抑制受体程序性死亡-1（PD-1）通过负调节T细胞功能和存活来维持免疫稳态。阻断PD-1会增加移植物抗宿主病（GVHD）的严重程度，但PD-1抑制和T细胞代谢之间的相互作用尚未得到充分研究。我们发现，小鼠和人类同种异体反应性T细胞同时上调PD-1的表达和活性氧（ROS）水平增加异基因骨髓移植后。这种PD-1HiROSHi表型对同种异体反应性T细胞具有特异性，并且在稳态增殖期间在同基因T细胞中未观察到。PD-1信号传导的阻断降低了线粒体H2 O2和总细胞ROS水平，并且PD-1驱动的ROS增加依赖于脂肪酸的氧化，因为用etomoxir治疗使PD-1阻断后ROS水平的变化无效。在PD-1的下游，ROS水平升高损害了T细胞的存活，这一过程被抗氧化剂逆转。此外，PD-1驱动的ROS变化是建立细胞对后续代谢抑制的易感性的基础，因为PD-1的阻断降低了后期F1 F0-ATP合酶调节的功效。这些数据表明，PD-1通过在依赖于脂肪氧化的过程中增加活性氧来促进同种异体反应性T细胞的凋亡。此外，PD-1的阻断破坏了后续代谢抑制的潜力，这是考虑到抗PD-1疗法在临床中的使用越来越多的重要考虑因素。
The co-inhibitory receptor programmed death-1 (PD-1) maintains immune homeostasis by negatively regulating T cell function and survival. Blockade of PD-1 increases the severity of graft-versus-host disease (GVHD), but the interplay between PD-1 inhibition and T cell metabolism is not well studied. We found that both murine and human alloreactive T cells concomitantly up-regulated PD-1 expression and increased levels of reactive oxygen species (ROS) following allogeneic bone marrow transplantation. This PD-1HiROSHi phenotype was specific to alloreactive T cells and was not observed in syngeneic T cells during homeostatic proliferation. Blockade of PD-1 signaling decreased both mitochondrial H2O2 and total cellular ROS levels and PD-1 driven increases in ROS were dependent upon the oxidation of fatty acids, as treatment with etomoxir nullified changes in ROS levels following PD-1 blockade. Downstream of PD-1, elevated ROS levels impaired T cell survival in a process reversed by anti-oxidants. Furthermore, PD-1 driven changes in ROS were fundamental to establishing a cell’s susceptibility to subsequent metabolic inhibition, as blockade of PD-1 decreased the efficacy of later F1F0-ATP synthase modulation. These data indicate that PD-1 facilitates apoptosis in alloreactive T cells by increasing reactive oxygen species in a process dependent upon the oxidation of fat. In addition, blockade of PD-1 undermines the potential for subsequent metabolic inhibition, an important consideration given the increasing use of anti-PD-1 therapies in the clinic.