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

Nat Metab. 2022 May;4(5):559-574. doi: 10.1038/s42255-022-00575-z.

Qi Liu ^# ¹, Fangming Zhu ^# ² ³, Xinnan Liu ^# ², Ying Lu ¹, Ke Yao ⁴, Na Tian ⁵, Lingfeng Tong ¹, David A Figge ⁶, Xiuwen Wang ⁷, Yichao Han ², Yakui Li ¹, Yemin Zhu ¹, Lei Hu ¹, Yingning Ji ¹, Nannan Xu ¹, Dan Li ², Xiaochuan Gu ⁸, Rui Liang ², Guifang Gan ⁹, Lifang Wu ¹, Ping Zhang ¹, Tianle Xu ¹⁰ ¹¹, Hui Hu ³, Zeping Hu ⁴, Huji Xu ⁷, Dan Ye ¹², Hui Yang ¹³, Bin Li ¹⁴, Xuemei Tong ¹⁵

Affiliations

1 Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
2 Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
3 Department of Microbiology, School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
4 School of Pharmaceutical Sciences, Tsinghua University, Beijing, China.
5 Department of Neurology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China.
6 Department of Pathology, School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
7 Department of Rheumatology and Immunology, Changzheng Hospital, Second Military Medical University, Shanghai, China.
8 Department of Orthopedics, Changhai Hospital, Second Military Medical University, Shanghai, China.
9 Shanghai Ninth People's Hospital, Department of Clinical Laboratories, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
10 Center for Brain Science of Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
11 Department of Anatomy and Physiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
12 Molecular and Cell Biology Lab of Key Laboratory of Molecular Medicine of Ministry of Education and Institutes of Biomedical Sciences, Shanghai Medical College, College of Life Science, Fudan University, Shanghai, China.
13 Department of Neurosurgery, Huashan Hospital, Institute for Translational Brain Research, Shanghai Key laboratory of Brain Function Restoration and Neural Regeneration, Shanghai Clinical Medical Center of Neurosurgery, MOE Frontiers Center for Brain Science, Shanghai Medical College, Fudan University, Shanghai, China. hui_yang@fudan.edu.cn.
14 Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China. binli@shsmu.edu.cn.
15 Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China. xuemeitong@shsmu.edu.cn.
# Contributed equally.

PMID: 35606596 DOI: 10.1038/s42255-022-00575-z

Abstract

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 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 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.

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