Cambridge Institute for Medical Research, University of Cambridge, Cambridge Biomedical Campus, Cambridge, CB2 0XY, UK.
Cell Signalling and Immunology Division, School of Life Sciences, University of Dundee, Dundee, DD1 5EH, UK.
Eur J Immunol. 2022 Nov;52(11):1776-1788. doi: 10.1002/eji.202249797. Epub 2022 Sep 26.
Bach2 codes for a transcriptional regulator exerting major influences on T cell-mediated immune regulation. Effector CTLs derived from in vitro activation of murine CD8 T cells showed increased proliferative and cytolytic capacity in the absence of BACH2. Before activation, BACH2-deficient splenic CD8 T cells had a higher abundance of memory and reduced abundance of naïve cells compared to wild-type. CTLs derived from central memory T cells were more potently cytotoxic than those derived from naïve T cells, but even within separated subsets, BACH2-deficiency conferred a cytotoxic advantage. Immunofluorescence and electron microscopy revealed larger granules in BACH2-deficient compared to wild-type CTLs, and proteomic analysis showed an increase in granule content, including perforin and granzymes. Thus, the enhanced cytotoxicity observed in effector CTLs lacking BACH2 arises not only from differences in their initial differentiation state but also inherent production of enlarged cytolytic granules. These results demonstrate how a single gene deletion can produce a CTL super-killer.
Bach2 编码一种转录调节因子，对 T 细胞介导的免疫调节有重要影响。在体外激活的小鼠 CD8 T 细胞中衍生的效应 CTL 在缺乏 BACH2 的情况下显示出增强的增殖和细胞毒性能力。在激活之前，与野生型相比，BACH2 缺陷的脾 CD8 T 细胞具有更高的记忆细胞丰度和更低的幼稚细胞丰度。来自中央记忆 T 细胞的 CTL 比来自幼稚 T 细胞的 CTL 更具细胞毒性，但即使在分离的亚群中，BACH2 缺陷也赋予了细胞毒性优势。免疫荧光和电子显微镜显示，与野生型 CTL 相比，BACH2 缺陷型 CTL 中的颗粒更大，蛋白质组学分析显示颗粒含量增加，包括穿孔素和颗粒酶。因此，在缺乏 BACH2 的效应 CTL 中观察到的增强的细胞毒性不仅源于其初始分化状态的差异，还源于固有产生的增大的细胞毒性颗粒。这些结果表明，单个基因缺失如何产生 CTL 超级杀手。
