供体T细胞STAT3缺陷使组织PD-L1依赖性预防移植物抗宿主病变，同时保留移植物抗白血病活性。
Donor T cell STAT3 deficiency enables tissue PD-L1-dependent prevention of graft-versus-host disease while preserving graft-versus-leukemia activity.
发表日期：2023 Aug 01
作者：
Qinjian Li, Xiaoqi Wang, Qingxiao Song, Shijie Yang, Xiwei Wu, Dongyun Yang, Isabelle J Marié, Hanjun Qin, Moqian Zheng, Ubaydah Nasri, Xiaohui Kong, Bixin Wang, Elizabeth Lizhar, Kaniel Cassady, Josh Tompkins, David Levy, Paul J Martin, Xi Zhang, Defu Zeng
来源：
Stem Cell Research & Therapy
摘要：
供体T细胞中的STAT3缺陷（STAT3-/-）可以防止移植物抗宿主病（GVHD），但对移植物抗白血病（GVL）活性和GVHD预防机制的影响尚不清楚。本研究使用GVHD小鼠模型表明，STAT3-/-供体T细胞仅引起轻度可逆的急性GVHD，同时以供体T细胞剂量依赖的方式保留对非易感急性淋巴细胞性白血病（ALL）细胞的GVL效应。GVHD预防依赖于程序死亡配体1/程序性死亡蛋白1（PD-L1/PD-1）信号传导。在GVHD目标组织中，STAT3缺陷扩大了PD-L1/PD-1对谷胱甘肽（GSH）/硫辛酸分子通路的抑制作用，该通路调节激活的T细胞的代谢重编程，减少了糖酵解和线粒体ATP产生以及增加了线粒体ROS产生和功能受损，导致特定组织中宿主抗原活化T细胞的特异性删除，从而防止GVHD。单纯的线粒体STAT3缺陷并未减少GSH的表达或防止GVHD。在淋巴组织中，宿主组织中PD-L1与PD-1的缺乏减弱了GSH/硫辛酸分子通路的抑制作用，尽管STAT3缺陷引起GSH产生的减少，却允许介导GVL活性的供体T细胞的功能。因此，供体T细胞中的STAT3缺陷增强了PD-1信号传导介导的抑制GSH/硫辛酸分子通路的能力，并加重GVHD目标组织中T细胞的功能障碍，同时保护淋巴组织中的T细胞，从而实现GVHD的预防并保留GVL效应。
STAT3 deficiency (STAT3-/-) in donor T cells prevents graft-versus-host disease (GVHD), but the impact on graft-versus-leukemia (GVL) activity and mechanisms of GVHD prevention remains unclear. Here, using murine models of GVHD, we show that STAT3-/- donor T cells induced only mild reversible acute GVHD while preserving GVL effects against nonsusceptible acute lymphoblastic leukemia (ALL) cells in a donor T cell dose-dependent manner. GVHD prevention depended on programmed death ligand 1/programmed cell death protein 1 (PD-L1/PD-1) signaling. In GVHD target tissues, STAT3 deficiency amplified PD-L1/PD-1 inhibition of glutathione (GSH)/Myc pathways that regulate metabolic reprogramming in activated T cells, with decreased glycolytic and mitochondrial ATP production and increased mitochondrial ROS production and dysfunction, leading to tissue-specific deletion of host-reactive T cells and prevention of GVHD. Mitochondrial STAT3 deficiency alone did not reduce GSH expression or prevent GVHD. In lymphoid tissues, the lack of host-tissue PD-L1 interaction with PD-1 reduced the inhibition of the GSH/Myc pathway despite reduced GSH production caused by STAT3 deficiency and allowed donor T cell functions that mediate GVL activity. Therefore, STAT3 deficiency in donor T cells augments PD-1 signaling-mediated inhibition of GSH/Myc pathways and augments dysfunction of T cells in GVHD target tissues while sparing T cells in lymphoid tissues, leading to prevention of GVHD while preserving GVL effects.