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

作者：Yixuan Wang, Xiang Xiao, Gangcheng Kong, Mou Wen, Guangchuan Wang, Rafik M. Ghobrial, Nianguo Dong, Wenhao Chen, Li X · 发表于：American Journal of Transplantation · 年份：2021 · DOI：10.1111/ajt.16861 · 被引用次数：21 · 研究领域：Immune Cell Function and Interaction、T-cell and B-cell Immunology、CAR-T cell therapy research

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 (CD44 high KLRG1 + ). 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.