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

Research output: Contribution to journalArticlepeer-review

Abstract

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 CD127KLRG1+ 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.

Original languageEnglish (US)
Article number882721
JournalFrontiers in immunology
Volume13
DOIs
StatePublished - Apr 19 2022

Keywords

  • allograft rejection
  • BATF
  • CD8 T cells
  • effector differentiation
  • memory
  • transplantation

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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