Overexpression of early T cell differentiation-specific transcription factors transforms the terminally differentiated effector T cells into less differentiated state
Overexpression of early T cell differentiation-specific transcription factors transforms the terminally differentiated effector T cells into less differentiated state
复制标题
早期 T 细胞分化特异性转录因子的过度表达将终末分化的效应 T 细胞转化为低分化状态
DOI：
10.1016/j.cellimm.2020.104118
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发表时间：
2020-07-01
影响因子：
4.3
通讯作者：
Wu, Fenglin
中科院分区：
文献类型：
--
作者：
Lu, Hua;Wang, Hui;Wu, Fenglin
输注的工程化T细胞的体内增殖和活力显著限制了过继细胞疗法对肿瘤的长期效果。据报道，T细胞的治疗功效和增殖潜力取决于T细胞的分化状态。处于进行性分化早期阶段的T细胞具有长寿命、强增殖潜力和重建完整T细胞亚群的能力。因此，它们更适合于过继免疫治疗。以前，通过抑制T细胞的进行性分化或通过两步编程难以获得足够数量的早期分化的T细胞。更有效的策略是直接将大量产生的容易获得的终末效应T（T-EFF）细胞重编程和去分化为早期T细胞。本研究试图在T-EFF细胞中过表达8种（候选）早期分化特异性转录因子（TF）（LEF 1、KLF 7、ID 3、EOMES、BCL 6、TCF 7、FOXP 1和FOXO 1），这些因子通过体外刺激激活，以促进去分化为早期T细胞。在同时过表达这些特异性TF的成熟T-EFF细胞中，T细胞分化标志物（CCR 7和CD 45 RO）的表达模式表现出向早期分化期间观察到的模式变化的趋势。转录组分析显示差异表达基因的功能主要集中在细胞周期、生长发育和效应子功能上。此外，许多与早期分化的T细胞相关的基因（如BCL 2和PIM 1）显著上调，而与T-EFF细胞的效应功能相关的基因（如GZMB，PRF 1和GNLY）显著下调。此外，过表达特征性TF的T-EFF细胞表现出增强的抗凋亡能力和减少的细胞因子（IFN-γ和TNF-α）分泌。基于这些结果，我们认为T-EFF细胞在过表达八种特异性TF后被重编程为分化程度较低的状态。
The in vivo proliferation and viability of transfused engineered T cells markedly limits the long-term effect of adoptive cell therapy on tumors. The therapeutic efficacy and proliferative potential of T cells are reported to be dependent on the differentiation status of T cells. The T cells at the early stage of progressive differentiation have a long lifespan, strong proliferative potential, and the ability to reconstruct intact T cell subsets. Thus, they are more suitable for adoptive immunotherapy. Previously, it was difficult to obtain a sufficient number of early differentiated T cells by inhibiting the progressive differentiation of T cells or by two-step programming. A more effective strategy is to directly reprogram and dedifferentiate the easily available terminal effector T (T-EFF) cells, which are generated in large numbers, into early T cells. This study attempted to overexpress eight (candidate) early differentiation-specific transcription factors (TFs) (LEF1, KLF7, ID3, EOMES, BCL6, TCF7, FOXP1, and FOXO1) in the T-EFF cells, which were activated by in vitro stimulation, to promote dedifferentiation into early T cells. In the mature T-EFF cells simultaneously overexpressing these specific TFs, the expression pattern of T cell differentiation markers (CCR7 and CD45RO) exhibited a tendency to change to the pattern observed during early differentiation. The transcriptome analysis revealed that the function of differentially expressed genes was mainly concentrated in the cell cycle, growth and development, and effector function. Moreover, many genes related to early differentiated T cells (such as BCL2 and PIM1) were significantly upregulated, while those related to the effector function of T-EFF cells were significantly downregulated (such as GZMB, PRF1, and GNLY). Additionally, the T-EFF cells overexpressing characteristic TFs exhibited enhanced anti-apoptotic capabilities and decreased secretion of cytokines (IFN-gamma and TNF-alpha). Based on these results, we believe that the T-EFF cells were reprogrammed into a less differentiated state after overexpression of the eight specific TFs.