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

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.