在Treg细胞中分级的Foxo1活性区分了瘤免疫与自发自身免疫
Chong T Luo1,2, Will Liao3, Saida Dadi1
1Immunology Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
Nature
|January 21, 2016
概括
调节性T细胞通常保持自我耐受性,但可以抑制抗瘤免疫力. 对Treg细胞迁移至关重要,使瘤能够逃避免疫. 操纵Foxo1信号可以破坏瘤耐受性而不会引起自身免疫.
科学领域:
- 免疫学
- 细胞生物学
- 癌症研究
背景情况:
- 表达Foxp3的调节性T (Treg) 细胞对于自我耐受性至关重要,但可以阻碍抗瘤免疫力.
- 非淋巴细胞组织中的激活Treg (aTreg) 细胞与静止Treg (rTreg) 细胞具有不同的功能,但它们的作用和调节尚不清楚.
研究的目的:
- 研究aTreg细胞的功能并探索其生成的潜在操纵.
- 阐明转录因子Foxo1在aTreg细胞介导的免疫耐受性和抗瘤反应中的作用.
主要方法:
- 在淋巴细胞和非淋巴细胞组织中对Treg细胞表型 (rTreg与aTreg) 的比较分析.
- 研究Treg细胞中的Foxo1表达,局部化和化.
- 在小鼠模型中利用Akt不敏感的Foxo1突变体的Treg细胞特异表达.
- 评估Foxo1操纵对免疫细胞群,自身免疫反应和瘤生长的影响.
主要成果:
- 发现Foxo1的失活对于aTreg细胞迁移和免疫耐受性至关重要,与其以前已知的抑制作用相反.
- aTreg细胞分化涉及对Foxo1依赖基因的抑制,减少了Foxo1的表达,并增强了Akt酸化.
- 在Treg细胞中表达Akt不敏感的Foxo1突变,破坏了它们向非淋巴细胞器官的指导,导致CD8(+) T细胞介导的自身免疫性疾病.
- 透瘤的Treg细胞显示了Fox1向基因的显著下调.
- 选择性地消耗了与瘤相关的Treg细胞,激活了效应体CD8 ((+) T细胞,并抑制了瘤生长,而没有诱导自身免疫.
结论:
- 对于aTreg细胞迁移,Foxo1的失活至关重要,它抑制了CD8的T细胞反应,并促进了瘤的免疫逃避.
- 可以调节Treg细胞中的Foxo信号通路以优先克服瘤诱导的免疫耐受性.
- 向Treg细胞中的Foxo1为增强抗瘤免疫提供了潜在的治疗策略.
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