Hyperlipidemia-induced metabolic changes in regulatory T cells result in altered function,European Journal of Immunology

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Hyperlipidemia-induced metabolic changes in regulatory T cells result in altered function
European Journal of Immunology ( IF 4.5 ) Pub Date : 2021-08-07 , DOI: 10.1002/eji.202049149
Michael Hyde _{1,

2,

3} , Jessamyn Bagley _{1,

2} , Philip W Hinds _{1,

3,

4} , Philip Tsichlis ₅ , John Iacomini _{1,

2,

3}

Affiliation

Regulatory T cells (Tregs) play a critical role in maintaining self-tolerance and controlling inflammation. However, physiologically relevant conditions that alter Treg function and drive disease pathogenesis are poorly understood and few have been defined. We have previously shown that induction of hyperlipidemia in mice results in changes in Tregs that reduce their function. Here, we set out to examine mechanisms by which hyperlipidemia alters Tregs. Using live-cell metabolic assays, we observed that induction of hyperlipidemia increases metabolism in Tregs but not conventional T cells. Increased metabolism resulted from preferential activation of the serine/threonine kinase Akt2 (PKB-β). Expression of a constitutively activated form of Akt2 in CD4 T cells was sufficient to increase glycolysis in Tregs and drive changes in Treg subsets. Induction of hyperlipidemia did not alter Treg metabolism in mice lacking Akt2. Activation of Akt2 was sufficient to drive the production of inflammatory cytokines by Tregs. We suggest that hyperlipidemia alters Treg function through effects on metabolism via Akt2 activation thereby promoting plasticity and decreased function of FoxP3+ T cells.

中文翻译：

高脂血症诱导的调节性 T 细胞代谢变化导致功能改变

调节性 T 细胞 (Tregs) 在维持自我耐受和控制炎症方面发挥着关键作用。然而，对改变 Treg 功能和驱动疾病发病机制的生理相关条件知之甚少，并且很少被定义。我们之前已经表明，诱导小鼠高脂血症会导致 Treg 发生变化，从而降低其功能。在这里，我们着手研究高脂血症改变 Treg 的机制。使用活细胞代谢分析，我们观察到高脂血症的诱导会增加 Tregs 而非传统 T 细胞的代谢。代谢增加是由于丝氨酸/苏氨酸激酶 Akt2 (PKB-β) 的优先激活所致。在 CD4 T 细胞中表达组成型激活形式的 Akt2 足以增加 Treg 中的糖酵解并驱动 Treg 亚群的变化。在缺乏 Akt2 的小鼠中，诱导高脂血症不会改变 Treg 代谢。Akt2 的激活足以驱动 Treg 产生炎性细胞因子。我们建议高脂血症通过 Akt2 激活影响代谢来改变 Treg 功能，从而促进 FoxP3+ T 细胞的可塑性和功能降低。

更新日期：2021-08-07

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