人类T细胞的全基因组CRISPR检测揭示了FOXP3的调节者
Kelvin Y Chen1, Tatsuya Kibayashi2,3, Ambre Giguelay4,5
1Laboratory of Experimental Immunology, Immunology Frontier Research Center, Osaka University, Osaka, Japan. chenk@ifrec.osaka-u.ac.jp.
Nature
|March 27, 2025
概括
调节性T细胞对于免疫平衡和自身免疫性疾病治疗至关重要. 这项研究确定了RBPJ-NCOR复合体作为关键调节剂,揭示了RBPJ废除的Treg细胞增强了稳定性和治疗潜力.
科学领域:
- 免疫学
- 细胞生物学
- 基因调控
背景情况:
- 通过FOXP3表达定义的调节性T (Treg) 细胞对于免疫耐受性和平衡至关重要.
- 目前用于在体外产生诱导的Treg (iTreg) 细胞的方法面临细胞稳定性的挑战,这限制了它们对自身免疫疾病的治疗应用.
- 对于开发更有效的基于细胞的疗法,了解控制Treg分化的遗传网络至关重要.
研究的目的:
- 确定影响人类T细胞FOXP3诱导的新基因调节因子.
- 在iTreg细胞分化,稳定性和功能中确定调节者的作用.
- 在自身免疫性疾病的临床前模型中评估操纵这些调节者的治疗潜力.
主要方法:
- 在人类T细胞中对全基因组CRISPR功能丧失进行查,以确定FOXP3调节基因.
- 用于基因扰乱的单细胞分辨率分析的Perturb-seq (Perturb-icCITE-seq).
- 在体外诱导iTreg细胞并评估其稳定性和功能.
- 在人体化小鼠模型中对RBPJ移除的iTreg细胞进行体内评估.
主要成果:
- RBPJ-NCOR抑制组合被确定为FOXP3表达的新型负调节剂.
- 通过FOXP3增强剂中枢神经系统2的DNA脱甲基化,RBPJ淘汰增强了iTreg细胞的分化和功能.
- RBPJ缺乏导致iTreg细胞的表型稳定性增加.
- 通过通过HDAC3调节FOXP3基因素乙化,抑制了RBPJ的诱导.
- 在人性化的小鼠模型中,RBPJ消去的iTreg细胞表现出优异的移植对宿主疾病抑制.
结论:
- RBPJ-NCOR复合体是FOXP3诱导和iTreg细胞稳定性的关键,特定的调节器.
- 针对RBPJ提供了一个有前途的策略,以提高基于iTreg细胞的疗法对自身免疫性疾病的疗效.
- 这些发现为FOXP3的调节机制提供了新的见解,并促进了采用细胞治疗的潜力.
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