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

Shuang Li, Dawei Zou, Wenhao Chen, Yating Cheng, Gavin W Britz, Yi-Lan Weng, Zhaoqian Liu

Frontiers in immunology 2022

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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. Copyright © 2022 Li, Zou, Chen, Cheng, Britz, Weng and Liu.

Citation

Shuang Li, Dawei Zou, Wenhao Chen, Yating Cheng, Gavin W Britz, Yi-Lan Weng, Zhaoqian Liu. Ablation of BATF Alleviates Transplant Rejection via Abrogating the Effector Differentiation and Memory Responses of CD8+ T Cells. Frontiers in immunology. 2022;13:882721