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.
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.
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DOI：
10.1111/ajt.16861
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发表时间：
2022-03
期刊：
影响因子：
--
通讯作者：
Li XC
中科院分区：
文献类型：
--
作者：
Wang Y;Xiao X;Kong G;Wen M;Wang G;Ghobrial RM;Dong N;Chen W;Li XC
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者，这一过程受到不同信号和转录因子的调节。在本研究中，我们研究了碱性亮氨酸拉链ATF样转录因子(BATF)家族成员在心脏移植模型中调节T细胞活性的作用，发现BATF和BATF3基因缺陷的小鼠(BATF−/−BATF3−/−小鼠)会自发接受长期不耐受的同种异体心脏移植。同样，将野生型T细胞过继转移到RAG1−/−宿主体内可引起心脏和皮肤移植物的迅速排斥反应，而BATF−/−BATF3−/−T细胞未能做到这一点。移植物浸润性细胞分析显示，BATF−/−BATF3−/−T细胞有移植物浸润性T细胞，但不能获得效应表型(CD44HighKLRG1+)。TCR转基因TEA模型的共转移实验表明，BATF−/−BATF3−/−T细胞不能在体内扩增，保持静止表型(CD62L+CD127+)，不能产生同种抗原刺激的效应性细胞因子，这与野生型T细胞形成了鲜明的对比。总之，我们的数据表明，BATF和BATF3是T效应器功能的关键调节因子，因此使它们成为移植环境中治疗干预的有吸引力的目标。
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 the present 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 TCR 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.
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