AMBRA1 Controls Regulatory T-Cell Differentiation and Homeostasis Upstream of the FOXO3-FOXP3 Axis
AMBRA1 Controls Regulatory T-Cell Differentiation and Homeostasis Upstream of the FOXO3-FOXP3 Axis
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DOI：
10.1016/j.devcel.2018.11.010
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发表时间：
2018-12-03
影响因子：
11.8
通讯作者：
Cecconi, Francesco
中科院分区：
文献类型：
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作者：
Becher, Juliane;Simula, Luca;Cecconi, Francesco
调节性T细胞（T-reg）是维持免疫耐受所必需的，并且是控制自身免疫性疾病易感性的关键参与者。转录因子FOXP 3的表达对于T-reg细胞的分化是必需的，并且对于它们的抑制功能是必不可少的。然而，人们仍然缺乏对其监管机制的了解。在这里，我们证明了促自噬蛋白AMBRA 1也是T细胞的关键调节剂，调节导致人类T-reg分化和维持的复杂网络。事实上，通过其与磷酸酶PP 2A相互作用的能力，AMBRA 1促进转录激活因子FOXO 3的稳定性，这反过来又触发FOXP 3转录。此外，我们发现AMBRA 1在体内通过调节肿瘤生长和多发性硬化小鼠模型中的T-reg细胞诱导发挥重要作用，从而突出了AMBRA 1在免疫稳态控制中的作用。
Regulatory T cells (T-reg) are necessary to maintain immunological tolerance and are key players in the control of autoimmune disease susceptibility. Expression of the transcription factor FOXP3 is essential for differentiation of T-reg cells and indispensable for their suppressive function. However, there is still a lack of knowledge about the mechanisms underlying its regulation. Here, we demonstrate that pro-autophagy protein AMBRA1 is also a key modulator of T cells, regulating the complex network that leads to human T-reg differentiation and maintenance. Indeed, through its ability to interact with the phosphatase PP2A, AMBRA1 promotes the stability of the transcriptional activator FOXO3, which, in turn, triggers FOXP3 transcription. Furthermore, we found that AMBRA1 plays a significant role in vivo by regulating T-reg cell induction in mouse models of both tumor growth and multiple sclerosis, thus highlighting the role of AMBRA1 in the control of immune homeostasis.