TOX是瘤特异性T细胞分化的关键调节剂
Andrew C Scott1,2, Friederike Dündar3,4, Paul Zumbo3,4
1Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Nature
|June 18, 2019
概括
核因子TOX调节瘤中的T细胞耗尽. 删除TOX阻止抑制受体的升级, 但没有恢复功能,
科学领域:
- 免疫学
- 分子生物学
- 癌症研究
背景情况:
- 瘤特异性CD8T细胞表现出功能障碍,这种状态与效应细胞或记忆T细胞不同.
- 了解T细胞耗尽的调节者对于改善抗瘤免疫力至关重要.
研究的目的:
- 确定瘤特异性T细胞分化和功能障碍的关键调节者.
- 阐明核因子TOX在瘤微环境中的T细胞耗尽中的作用.
主要方法:
- 在慢性病毒感染的功能失调的TST细胞和耗尽的T细胞中分析TOX表达.
- 实验室实验涉及T细胞的子宫外TOX表达.
- 在瘤内的TST细胞中Tox的遗传删除.
- 对基因表达,染色质可访问性和转录因子概况的评估.
主要成果:
- TOX在功能障碍的TST细胞中表达很高,并由慢性T细胞受体刺激和NFAT激活驱动.
- 宫外TOX表达诱导T细胞耗尽的转录程序.
- 毒素删除取消了疲劳计划,防止抑制受体的上调和维持TCF-1表达.
- 尽管免疫类型没有耗尽,但已删除毒素的TST细胞仍然存在功能障碍,并且无法在瘤中持续存在.
结论:
- TOX是T细胞疲劳的关键调节者,调节抑制受体的上升.
- 通过TOX对抑制受体的调节与效应器功能的丧失无关.
- 在癌症等慢性抗原暴露环境中,TOX诱导的疲劳计划可以防止T细胞过度刺激和激活诱导的细胞死亡,尽管它会损害T细胞的持久性.
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