6-Phosphogluconate dehydrogenase (6PGD), a key checkpoint in reprogramming of regulatory T cells metabolism and function

eLife

Teresa Cassel¹  Richard M Higashi¹  Teresa W-M Fan¹  Saeed Daneshmandi²  Pankaj Seth² 

[1] Center for Environmental and Systems Biochemistry, University of Kentucky, Lexington, United States;Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, United States;Division of Interdisciplinary Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, United States;

关键词: regulatory T cell;    metabolism;    6PGD;    immunoregulation;    glucose;    pentose phosphate pathway;    Mouse;   

DOI  :  10.7554/eLife.67476

来源: eLife Sciences Publications, Ltd

【 摘 要 】

Cellular metabolism has key roles in T cells differentiation and function. CD4+ T helper-1 (Th1), Th2, and Th17 subsets are highly glycolytic while regulatory T cells (Tregs) use glucose during expansion but rely on fatty acid oxidation for function. Upon uptake, glucose can enter pentose phosphate pathway (PPP) or be used in glycolysis. Here, we showed that blocking 6-phosphogluconate dehydrogenase (6PGD) in the oxidative PPP resulted in substantial reduction of Tregs suppressive function and shifts toward Th1, Th2, and Th17 phenotypes which led to the development of fetal inflammatory disorder in mice model. These in turn improved anti-tumor responses and worsened the outcomes of colitis model. Metabolically, 6PGD blocked Tregs showed improved glycolysis and enhanced non-oxidative PPP to support nucleotide biosynthesis. These results uncover critical role of 6PGD in modulating Tregs plasticity and function, which qualifies it as a novel metabolic checkpoint for immunotherapy applications.

【 授权许可】

CC BY