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首页> 外文期刊>Cellular immunology >Overexpression of early T cell differentiation-specific transcription factors transforms the terminally differentiated effector T cells into less differentiated state
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Overexpression of early T cell differentiation-specific transcription factors transforms the terminally differentiated effector T cells into less differentiated state

机译：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细胞转化为较差的分化状态

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摘要

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.
机译：输注的工程化T细胞的体内增殖和生存能力明显限制了过继细胞疗法对肿瘤的长期疗效。据报道，T细胞的治疗效果和增殖潜能取决于T细胞的分化状态。处于进行性分化早期的T细胞具有较长的寿命、较强的增殖潜能和重建完整T细胞亚群的能力。因此，它们更适合过继免疫治疗。以前，通过抑制T细胞的逐渐分化或两步编程很难获得足够数量的早期分化T细胞。一种更有效的策略是直接将容易获得的终端效应T（T-EFF）细胞重新编程并去分化为早期T细胞，这些细胞大量产生。本研究试图在体外刺激激活的T-EFF细胞中过度表达八种（候选）早期分化特异性转录因子（TF）（LEF1、KLF7、ID3、EOMES、BCL6、TCF7、FOXP1和FOXO1），以促进脱分化为早期T细胞。在同时过度表达这些特异性TFs的成熟T-EFF细胞中，T细胞分化标记物（CCR7和CD45RO）的表达模式呈现出向早期分化期间观察到的模式变化的趋势。转录组分析表明，差异表达基因的功能主要集中在细胞周期、生长发育和效应器功能。此外，许多与早期分化T细胞相关的基因（如BCL2和PIM1）显著上调，而与T-EFF细胞效应器功能相关的基因（如GZMB、PRF1和GNLY）显著下调。此外，过度表达特异性TFs的T-EFF细胞表现出增强的抗凋亡能力，并减少细胞因子（IFN-γ和TNF-α）的分泌。基于这些结果，我们认为在过度表达八种特异性TFs后，T-EFF细胞被重新编程为分化程度较低的状态。

著录项

  • 来源
    《Cellular immunology》 |2020年第1期|共10页
  • 作者

    Lu Hua; Wang Hui; Yan Lijun; Shao Hongwei; Zhang Wenfeng; Shen Han; Bo Huaben; Tao Changli; Xia Shengfang; Wu Fenglin;

  • 作者单位

    Guangdong Pharmaceut Univ Guangdong Prov Key Lab Biotechnol Drug Candidates Guangzhou Peoples R;

    Guangdong Pharmaceut Univ Guangdong Prov Key Lab Biotechnol Drug Candidates Guangzhou Peoples R;

    Guangdong Pharmaceut Univ Guangdong Prov Key Lab Biotechnol Drug Candidates Guangzhou Peoples R;

    Guangdong Pharmaceut Univ Guangdong Prov Key Lab Biotechnol Drug Candidates Guangzhou Peoples R;

    Guangdong Pharmaceut Univ Guangdong Prov Key Lab Biotechnol Drug Candidates Guangzhou Peoples R;

    Guangdong Pharmaceut Univ Guangdong Prov Key Lab Biotechnol Drug Candidates Guangzhou Peoples R;

    Guangdong Pharmaceut Univ Guangdong Prov Key Lab Biotechnol Drug Candidates Guangzhou Peoples R;

    Guangdong Pharmaceut Univ Guangdong Prov Key Lab Biotechnol Drug Candidates Guangzhou Peoples R;

    Guangdong Pharmaceut Univ Guangdong Prov Key Lab Biotechnol Drug Candidates Guangzhou Peoples R;

    Guangdong Pharmaceut Univ Guangdong Prov Key Lab Biotechnol Drug Candidates Guangzhou Peoples R;

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  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 细胞生物学;
  • 关键词

    effector T cell; Specific transcription factor; Overexpression; Dedifferentiation;

    机译：效应器T细胞;特定转录因子;过度表达;消化不良;

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