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

被引:4
作者
Li, Shuang
Zou, Dawei
Chen, Wenhao
Cheng, Yating
Britz, Gavin W.
Weng, Yi-Lan
Liu, Zhaoqian
机构
[1] Department of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, and National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha
[2] Institute of Clinical Pharmacology, Central South University, Changsha
[3] Department of Neurosurgery, Houston Methodist Neurological Institute, Houston, TX
[4] Center for Neuroregeneration, Houston Methodist Research Institute, Houston, TX
[5] Immunobiology Transplant Science Center, Department of Surgery, Houston Methodist Research Institute Institute for Academic Medicine, Houston Methodist Hospital, Houston, TX
关键词
BATF; CD8(+) T cells; effector differentiation; allograft rejection; transplantation; memory; TRANSCRIPTION FACTOR IRF4; REGULATORY FACTOR 4; TERMINAL DIFFERENTIATION; PERIPHERAL-BLOOD; BET; CHECKPOINT; EXPRESSION; COOPERATE; EXPANSION; ZEB2;
D O I
10.3389/fimmu.2022.882721
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
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.
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页数:12
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