美国波士顿儿童医院Talal A. Chatila研究团队发现功能性重塑Foxp3缺失调节性T细胞功能的方法。这一研究成果发表在2019年9月出版的国际学术期刊《自然—免疫学》上。

转录因子Foxp3缺失的调节性T细胞（T_reg细胞）缺乏抑制功能并且表现出效应T（T_eff）细胞样表型。研究人员证明Foxp3缺失调节代谢检查点激酶哺乳动物雷帕霉素（mTOR）复合物2（mTORC2）信号传导的靶标，并产生有氧糖酵解和氧化磷酸化的增加。在Foxp3缺陷型T_reg细胞中特异性缺失mTORC2衔接基因Rictor能够以Foxo1转录因子依赖性方式改善疾病。Rictor缺陷重建Treg细胞遗传回路的一个亚群并抑制T_eff细胞样糖酵解和呼吸程序，从而导致免疫失调。用mTOR抑制剂治疗FOXP3缺陷患者的T_reg细胞同样拮抗其T_eff细胞样程序并恢复抑制功能。

因此，通过靶向其代谢途径，可以在Foxp3缺陷型T_reg细胞中重建调节功能，从而为恢复T_reg细胞疾病的耐受性提供了机会。

附：英文原文

Title: Functional reprogramming of regulatory T cells in the absence of Foxp3

Author: Louis-Marie Charbonnier, Ye Cui, Emmanuel Stephen-Victor, Hani Harb, David Lopez, Jack J. Bleesing, Maria I. Garcia-Lloret, Karin Chen, Ahmet Ozen, Peter Carmeliet, Ming O. Li, Matteo Pellegrini, Talal A. Chatila

Issue&Volume: Volume 20 Issue 9

Abstract: Regulatory T cells (Treg cells) deficient in the transcription factor Foxp3 lack suppressor function and manifest an effector T (Teff) cell–like phenotype. We demonstrate that Foxp3 deficiency dysregulates metabolic checkpoint kinase mammalian target of rapamycin (mTOR) complex 2 (mTORC2) signaling and gives rise to augmented aerobic glycolysis and oxidative phosphorylation. Specific deletion of the mTORC2 adaptor gene Rictor in Foxp3-deficient Treg cells ameliorated disease in a Foxo1 transcription factor–dependent manner. Rictor deficiency re-established a subset of Treg cell genetic circuits and suppressed the Teff cell–like glycolytic and respiratory programs, which contributed to immune dysregulation. Treatment of Treg cells from patients with FOXP3 deficiency with mTOR inhibitors similarly antagonized their Teff cell–like program and restored suppressive function. Thus, regulatory function can be re-established in Foxp3-deficient Treg cells by targeting their metabolic pathways, providing opportunities to restore tolerance in Treg cell disorders.

DOI: 10.1038/s41590-019-0442-x

Source:https://www.nature.com/articles/s41590-019-0442-x