Non-oxidative pentose phosphate pathway controls regulatory T cell function by integrating metabolism and epigenetics
Non-oxidative pentose phosphate pathway controls regulatory T cell function by integrating metabolism and epigenetics
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DOI：
10.1038/s42255-022-00575-z
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发表时间：
2022-05-23
影响因子：
20.8
通讯作者：
Tong, Xuemei
中科院分区：
文献类型：
--
作者：
Liu, Qi;Zhu, Fangming;Tong, Xuemei
调节性T（T-reg）细胞对于维持免疫稳态和预防自身免疫至关重要。在这里，我们表明非氧化戊糖磷酸途径（PPP）调节T-reg功能以防止自身免疫。T-reg细胞中非氧化PPP不可或缺的酶--转酮醇酶（transketolase，TKT）的缺失导致小鼠致命的自身免疫性疾病，尽管T-reg数量正常且Foxp 3表达水平正常，但T-reg抑制能力受损。从机制上讲，TKT缺乏引起的糖酵解减少和氧化应激增强触发了过量的脂肪酸和氨基酸催化剂，导致不受控制的氧化磷酸化和线粒体适应性受损。由于TCA循环活性降低导致的a-KG水平降低导致DNA超甲基化，从而限制TKT缺陷型T-reg细胞的功能基因表达和抑制活性。我们还发现，TKT水平在自身免疫性疾病患者的T-reg细胞中经常下调。我们的研究将非氧化PPP确定为控制T-reg功能的代谢和表观遗传过程的整合者。
Regulatory T (T-reg) cells are critical for maintaining immune homeostasis and preventing autoimmunity. Here, we show that the non-oxidative pentose phosphate pathway (PPP) regulates T-reg function to prevent autoimmunity. Deletion of transketolase (TKT), an indispensable enzyme of non-oxidative PPP, in T-reg cells causes a fatal autoimmune disease in mice, with impaired T-reg suppressive capability despite regular T-reg numbers and normal Foxp3 expression levels. Mechanistically, reduced glycolysis and enhanced oxidative stress induced by TKT deficiency triggers excessive fatty acid and amino acid catabolism, resulting in uncontrolled oxidative phosphorylation and impaired mitochondrial fitness. Reduced alpha-KG levels as a result of reductive TCA cycle activity leads to DNA hypermethylation, thereby limiting functional gene expression and suppressive activity of TKT-deficient T-reg cells. We also find that TKT levels are frequently downregulated in T-reg cells of people with autoimmune disorders. Our study identifies the non-oxidative PPP as an integrator of metabolic and epigenetic processes that control T-reg function.