TY - JOUR TI - 6-Phosphogluconate dehydrogenase (6PGD), a key checkpoint in reprogramming of regulatory T cells metabolism and function AU - Daneshmandi, Saeed AU - Cassel, Teresa AU - Higashi, Richard M AU - Fan, Teresa W-M AU - Seth, Pankaj A2 - Sarin, Apurva A2 - Rath, Satyajit A2 - Sarin, Apurva A2 - Piconese, Silvia VL - 10 PY - 2021 DA - 2021/10/28 SP - e67476 C1 - eLife 2021;10:e67476 DO - 10.7554/eLife.67476 UR - https://doi.org/10.7554/eLife.67476 AB - 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. KW - regulatory T cell KW - metabolism KW - 6PGD KW - immunoregulation KW - glucose KW - pentose phosphate pathway JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -