Department of Immunobiology, Yale University School of Medicine, New Haven, CT.
Department of Genetics and Yale Stem Cell Center, Yale University School of Medicine, New Haven, CT.
J Exp Med. 2018 Apr 2;215(4):1153-1168. doi: 10.1084/jem.20171352. Epub 2018 Feb 15.
Long-term immunity depends partly on the establishment of memory CD8 T cells. We identified a counterregulatory network between the homologous transcription factors ZEB1 and ZEB2 and the microRNA family, which modulates effector CD8 T cell fates. Unexpectedly, and had reciprocal expression patterns and were functionally uncoupled in CD8 T cells. ZEB2 promoted terminal differentiation, whereas ZEB1 was critical for memory T cell survival and function. Interestingly, the transforming growth factor β (TGF-β) and miR-200 family members, which counterregulate the coordinated expression of and during the epithelial-to-mesenchymal transition, inversely regulated and expression in CD8 T cells. TGF-β induced and sustained expression in maturing memory CD8 T cells. Meanwhile, both TGF-β and family members selectively inhibited Additionally, the miR-200 family was necessary for optimal memory CD8 T cell formation. These data outline a previously unknown genetic pathway in CD8 T cells that controls effector and memory cell fate decisions.
长期免疫部分取决于记忆 CD8 T 细胞的建立。我们发现了同源转录因子 ZEB1 和 ZEB2 与 microRNA 家族之间的一个负反馈调节网络，该网络调节效应 CD8 T 细胞的命运。出乎意料的是， 和 在 CD8 T 细胞中呈现出相互逆转的表达模式，并在功能上解耦。ZEB2 促进终末分化，而 ZEB1 对于记忆 T 细胞的存活和功能至关重要。有趣的是，转化生长因子-β（TGF-β）和 miR-200 家族成员在上皮细胞-间充质转化过程中协同调节 和 的表达，在 CD8 T 细胞中则相反地调节 和 的表达。TGF-β 在成熟的记忆 CD8 T 细胞中诱导并持续表达 。同时，TGF-β 和 家族成员选择性地抑制 。此外，miR-200 家族对于最优的记忆 CD8 T 细胞形成是必需的。这些数据描绘了一个在 CD8 T 细胞中控制效应器和记忆细胞命运决定的未知遗传途径。
