Department of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, and National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China.
Institute of Clinical Pharmacology, Central South University, Changsha, China.
Front Immunol. 2022 Apr 19;13:882721. doi: 10.3389/fimmu.2022.882721. eCollection 2022.
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. 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.
同种异体 CD8 T 细胞在移植物排斥中起重要作用，但它们的效应分化和功能如何在转录水平上受到调控还不完全清楚。在此，我们鉴定了碱性亮氨酸拉链 ATF 样转录因子（BATF）作为一个关键的转录因子，驱动同种异体 CD8 T 细胞的效应程序。我们发现 BATF 在浸润移植物的 CD8 T 细胞中高度表达，其在 CD8 T 细胞中的缺失显著延长了完全 MHC 错配移植模型中的皮肤移植物存活期。为了研究 BATF 如何决定同种异体 CD8 T 细胞的反应，我们将 BATF 和野生型（WT）CD8 T 细胞以 1:1 的比例混合，并在皮肤移植前 1 天过继转移到 B6. 小鼠中。与排斥反应高峰期的 WT CD8 T 细胞相比，BATF CD8 T 细胞表现出功能失调的表型，表现在未能分化为 CD127KLRG1 终末效应器，增殖能力和产生促炎细胞因子/细胞毒性分子受损，以及浸润移植物的能力降低。与效应分化失败相关，BATF CD8 T 细胞大量保留 TCF1 表达，并显著低表达 T-bet、TOX 和 Ki67。在记忆阶段，同种异体抗原再次刺激时，BATF 缺陷的 CD8 T 细胞表现出效应分化受损。因此，BATF 是决定移植环境中同种异体 CD8 T 细胞终末分化和记忆反应的关键转录决定因素。靶向 CD8 T 细胞中的 BATF 可能是促进移植接受的一种有吸引力的治疗方法。
