TY - JOUR
T1 - 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
AU - Wang, Yixuan
AU - Xiao, Xiang
AU - Kong, Gangcheng
AU - Wen, Mou
AU - Wang, Guangchuan
AU - Ghobrial, Rafik M.
AU - Dong, Nianguo
AU - Chen, Wenhao
AU - Li, Xian C.
N1 - Funding Information:
The authors thank Ms. Laurie Minze for excellent operational supports and Dr. Elizabeth Taparowsky at Purdue University for valuable reagents. This work was supported by the National Institutes of Health grants R01AI129906.
Funding Information:
The authors thank Ms. Laurie Minze for excellent operational supports and Dr. Elizabeth Taparowsky at Purdue University for valuable reagents. This work was supported by the National Institutes of Health grants R01AI129906.
Publisher Copyright:
© 2021 The American Society of Transplantation and the American Society of Transplant Surgeons.
PY - 2022/2
Y1 - 2022/2
N2 - 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.
AB - 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.
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U2 - 10.1111/ajt.16861
DO - 10.1111/ajt.16861
M3 - Article
C2 - 34599765
AN - SCOPUS:85117033396
VL - 22
SP - 414
EP - 426
JO - American Journal of Transplantation
JF - American Journal of Transplantation
SN - 1600-6135
IS - 2
ER -