Institut de Génétique Moléculaire de Montpellier, Univ Montpellier, CNRS, Montpellier, France.
Institut de Génétique Moléculaire de Montpellier, Univ Montpellier, CNRS, Montpellier, France; Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Australia.
Cell Rep. 2021 Nov 2;37(5):109911. doi: 10.1016/j.celrep.2021.109911.
Suppressive regulatory T cell (Treg) differentiation is controlled by diverse immunometabolic signaling pathways and intracellular metabolites. Here we show that cell-permeable α-ketoglutarate (αKG) alters the DNA methylation profile of naive CD4 T cells activated under Treg polarizing conditions, markedly attenuating FoxP3+ Treg differentiation and increasing inflammatory cytokines. Adoptive transfer of these T cells into tumor-bearing mice results in enhanced tumor infiltration, decreased FoxP3 expression, and delayed tumor growth. Mechanistically, αKG leads to an energetic state that is reprogrammed toward a mitochondrial metabolism, with increased oxidative phosphorylation and expression of mitochondrial complex enzymes. Furthermore, carbons from ectopic αKG are directly utilized in the generation of fatty acids, associated with lipidome remodeling and increased triacylglyceride stores. Notably, inhibition of either mitochondrial complex II or DGAT2-mediated triacylglyceride synthesis restores Treg differentiation and decreases the αKG-induced inflammatory phenotype. Thus, we identify a crosstalk between αKG, mitochondrial metabolism and triacylglyceride synthesis that controls Treg fate.
抑制性调节性 T 细胞 (Treg) 的分化受多种免疫代谢信号通路和细胞内代谢物的控制。在这里，我们表明，细胞通透性的 α-酮戊二酸 (αKG) 改变了在 Treg 极化条件下激活的初始 CD4 T 细胞的 DNA 甲基化谱，显著减弱了 FoxP3+Treg 的分化，并增加了炎症细胞因子。将这些 T 细胞过继转移到荷瘤小鼠中会导致肿瘤浸润增强、FoxP3 表达减少和肿瘤生长延迟。在机制上，αKG 导致能量状态向线粒体代谢重新编程，氧化磷酸化增加，线粒体复合物酶的表达增加。此外，来自异位 αKG 的碳直接用于脂肪酸的生成，与脂质组重塑和三酰基甘油储存增加有关。值得注意的是，抑制线粒体复合物 II 或 DGAT2 介导的三酰基甘油合成可恢复 Treg 的分化，并降低 αKG 诱导的炎症表型。因此，我们确定了 αKG、线粒体代谢和三酰基甘油合成之间的相互作用，控制了 Treg 的命运。
