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Genetically targeting the BATF family transcription factors BATF and BATF3 in the mouse abrogates effector T cell activities and enables long-term heart allograft survival
American Journal of Transplantation ( IF 8.8 ) Pub Date : 2021-10-02 , DOI: 10.1111/ajt.16861
Yixuan Wang 1, 2 , Xiang Xiao 1 , Gangcheng Kong 1 , Mou Wen 1 , Guangchuan Wang 1 , Rafik M Ghobrial 1, 3 , Nianguo Dong 1, 2 , Wenhao Chen 1, 3 , Xian C Li 1, 3
Affiliation  

T cells must be activated and become effectors first before executing allograft rejection, a process that is regulated by diverse signals and transcription factors. In this study, we studied the basic leucine zipper ATF-like transcription factor (BATF) family members in regulating T cell activities in a heart transplant model and found that mice deficient for both BATF and BATF3 (Batf−/−Batf3−/− mice) spontaneously accept the heart allografts long-term without tolerizing therapies. Similarly, adoptive transfer of wild type T cells into Rag1−/− hosts induced prompt rejection of heart and skin allografts, whereas the Batf−/−Batf3−/− T cells failed to do so. Analyses of graft-infiltrating cells showed that Batf−/−Batf3−/− T cells infiltrate the graft but fail to acquire an effector phenotype (CD44highKLRG1+). Co-transfer experiments in a T cell receptor transgenic TEa model revealed that the Batf−/−Batf3−/− T cells fail to expand in vivo, retain a quiescent phenotype (CD62L+CD127+), and unable to produce effector cytokines to alloantigen stimulation, which contrasted sharply to that of wild type T cells. Together, our data demonstrate that the BATF and BATF3 are critical regulators of T effector functions, thus making them attractive targets for therapeutic interventions in transplant settings.

中文翻译:

基因靶向小鼠中的 BATF 家族转录因子 BATF 和 BATF3 可消除效应 T 细胞活性并使心脏同种异体移植物长期存活

在执行同种异体移植排斥反应之前,T 细胞必须首先被激活并成为效应细胞,这一过程受多种信号和转录因子的调节。在这项研究中,我们研究了在心脏移植模型中调节 T 细胞活性的基本亮氨酸拉链 ATF 样转录因子 (BATF) 家族成员,发现小鼠缺乏 BATF 和 BATF3 ( Batf −/− Batf3 −/−小鼠) 长期自发地接受同种异体心脏移植而无需耐受治疗。同样,将野生型 T 细胞过继转移到Rag1 -/-宿主中会引起心脏和皮肤同种异体移植物的迅速排斥,而Batf -/- Batf3 -/-T 细胞无法做到这一点。移植物浸润细胞分析显示Batf -/- Batf3 -/- T 细胞浸润移植物但未能获得效应表型(CD44KLRG1 +)。T 细胞受体转基因 TEa 模型中的共转移实验表明,Batf -/- Batf3 -/- T 细胞无法在体内扩增,保留静止表型(CD62L + CD127 +), 并且不能产生效应细胞因子来刺激同种异体抗原,这与野生型 T 细胞形成鲜明对比。总之,我们的数据表明 BATF 和 BATF3 是 T 效应器功能的关键调节器,因此使它们成为移植环境中治疗干预的有吸引力的目标。
更新日期:2021-10-02
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