Non-oxidative pentose phosphate pathway controls regulatory T cell function by integrating metabolism and epigenetics

Qi Liu, Fangming Zhu, Xinnan Liu, Ying Lu, Ke Yao, Na Tian, Lingfeng Tong, David A. Figge, Xiuwen Wang, Yichao Han, Yakui Li, Yemin Zhu, Lei Hu, Yingning Ji, Nannan Xu, Dan Li, Xiaochuan Gu, Rui Liang, Guifang Gan, Lifang WuPing Zhang, Tianle Xu, Hui Hu, Zeping Hu, Huji Xu, Dan Ye, Hui Yang, Bin Li, Xuemei Tong

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Regulatory T (Treg) cells are critical for maintaining immune homeostasis and preventing autoimmunity. Here, we show that the non-oxidative pentose phosphate pathway (PPP) regulates Treg function to prevent autoimmunity. Deletion of transketolase (TKT), an indispensable enzyme of non-oxidative PPP, in Treg cells causes a fatal autoimmune disease in mice, with impaired Treg suppressive capability despite regular Treg 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 α-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 Treg cells. We also find that TKT levels are frequently downregulated in Treg cells of people with autoimmune disorders. Our study identifies the non-oxidative PPP as an integrator of metabolic and epigenetic processes that control Treg function.

Original languageEnglish (US)
Pages (from-to)559-574
Number of pages16
JournalNature Metabolism
Volume4
Issue number5
DOIs
StatePublished - May 2022
Externally publishedYes

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism
  • Cell Biology
  • Physiology (medical)

Fingerprint

Dive into the research topics of 'Non-oxidative pentose phosphate pathway controls regulatory T cell function by integrating metabolism and epigenetics'. Together they form a unique fingerprint.

Cite this