The transcription factor Myb enhances CD8+ T cell stemness and antitumor immunity. The transcription factor Myb enhances CD8+ T cell stemness and antitumor immunity

Stem cells are maintained by transcriptional programs promoting self-renewal and repressing differentiation. Here, we show that the transcription factor Myb is essential for generating and maintaining stem cells within the CD8+ T-cell memory compartment. We found that, following viral infection, CD8+ T cells lacking Myb underwent terminal differentiation and exhibited impaired capacity to form CD62L+ stem cell-like memory cells. Myb acted both as a transcriptional activator of Tcf7 to enhance the development of memory cells and as a repressor of effector differentiation through Zeb2 suppression. Myb mutants’ complementation revealed that the Myb transactivation domain was necessary to restrain terminal differentiation, whereas the negative regulatory domain was critical for cell survival. Conversely, Myb overexpression enhanced CD8+ T-cell memory formation, polyfunctionality, and recall responses promoting curative antitumor immunity. These findings identify Myb as a pivotal regulator of CD8+ T-cell stemness and highlight the therapeutic potential of increasing Myb activity in CD8+ T cells. Overall design: We compared the gene expression profiles of Myb-defiecient CD8+ T cells with those of Myb-sufficient CD8+ T cells

干细胞通过促进自我更新并抑制分化的转录程序得以维持。本研究表明，转录因子（transcription factor）Myb对于CD8+ T细胞（CD8+ T cell）记忆池内干细胞的产生与维持至关重要。本研究观察到，在病毒感染后，缺失Myb的CD8+ T细胞会发生终末分化（terminal differentiation），且形成CD62L阳性干细胞样记忆细胞（CD62L+ stem cell-like memory cell）的能力受损。Myb既作为Tcf7的转录激活因子（transcriptional activator）以促进记忆细胞的发育，又通过抑制Zeb2阻遏效应分化（effector differentiation）过程。对Myb突变体的互补实验显示，Myb的反式激活结构域（transactivation domain）是抑制终末分化所必需的，而负调控结构域（negative regulatory domain）则对细胞存活（cell survival）至关重要。与之相反，Myb过表达（overexpression）可增强CD8+ T细胞的记忆形成能力、细胞多功能性（polyfunctionality）以及介导治愈性抗肿瘤免疫（curative antitumor immunity）的回忆应答（recall response）。本研究证实Myb是CD8+ T细胞干性（stemness）的关键调控因子，并凸显了在CD8+ T细胞中增强Myb活性的治疗潜力（therapeutic potential）。总体实验设计：我们比较了Myb缺陷型CD8+ T细胞与Myb功能正常型CD8+ T细胞的基因表达谱。