Ablation of BATF Alleviates Transplant Rejection via Abrogating the Effector Differentiation and Memory Responses of CD8(+) T Cells

Allogeneic CD8(+) T cells are prominently involved in allograft rejection, but how their effector differentiation and function are regulated at a transcriptional level is not fully understood. Herein, we identified the basic leucine zipper ATF-like transcription factor (BATF) as a key transcription factor that drives the effector program of allogeneic CD8(+) T cells. We found that BATF is highly expressed in graft-infiltrating CD8(+) T cells, and its ablation in CD8(+) T cells significantly prolonged skin allograft survival in a fully MHC-mismatched transplantation model. To investigate how BATF dictates allogeneic CD8(+) T cell response, BATF(–/–) and wild-type (WT) CD8(+) T cells were mixed in a 1:1 ratio and adoptively transferred into B6.Rag1 (–/–) mice 1 day prior to skin transplantation. Compared with WT CD8(+) T cells at the peak of rejection response, BATF(–/–) CD8(+) T cells displayed a dysfunctional phenotype, evident by their failure to differentiate into CD127(–)KLRG1(+) terminal effectors, impaired proliferative capacity and production of pro-inflammatory cytokines/cytotoxic molecules, and diminished capacity to infiltrate allografts. In association with the failure of effector differentiation, BATF(–/–) CD8(+) T cells largely retained TCF1 expression and expressed significantly low levels of T-bet, TOX, and Ki67. At the memory phase, BATF-deficient CD8(+) T cells displayed impaired effector differentiation upon allogeneic antigen re-stimulation. Therefore, BATF is a critical transcriptional determinant that governs the terminal differentiation and memory responses of allogeneic CD8(+) T cells in the transplantation setting. Targeting BATF in CD8(+) T cells may be an attractive therapeutic approach to promote transplant acceptance.