6-Phosphogluconate dehydrogenase (6PGD), a key checkpoint in reprogramming of regulatory T cells metabolism and function
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...
| Main Authors: | , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
eLife Sciences Publications Ltd
2021-10-01
|
| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/67476 |
| _version_ | 1811227351829184512 |
|---|---|
| author | Saeed Daneshmandi Teresa Cassel Richard M Higashi Teresa W-M Fan Pankaj Seth |
| author_facet | Saeed Daneshmandi Teresa Cassel Richard M Higashi Teresa W-M Fan Pankaj Seth |
| author_sort | Saeed Daneshmandi |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-12T09:41:06Z |
| format | Article |
| id | doaj.art-851c6bd2a26549a4b642403b49029a4d |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T09:41:06Z |
| publishDate | 2021-10-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-851c6bd2a26549a4b642403b49029a4d2022-12-22T03:38:04ZengeLife Sciences Publications LtdeLife2050-084X2021-10-011010.7554/eLife.674766-Phosphogluconate dehydrogenase (6PGD), a key checkpoint in reprogramming of regulatory T cells metabolism and functionSaeed Daneshmandi0https://orcid.org/0000-0001-7817-3006Teresa Cassel1https://orcid.org/0000-0003-1700-932XRichard M Higashi2Teresa W-M Fan3https://orcid.org/0000-0002-7292-8938Pankaj Seth4Department 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 StatesCenter for Environmental and Systems Biochemistry, University of Kentucky, Lexington, United StatesCenter for Environmental and Systems Biochemistry, University of Kentucky, Lexington, United StatesCenter for Environmental and Systems Biochemistry, University of Kentucky, Lexington, United StatesDepartment 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 StatesCellular 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.https://elifesciences.org/articles/67476regulatory T cellmetabolism6PGDimmunoregulationglucosepentose phosphate pathway |
| spellingShingle | Saeed Daneshmandi Teresa Cassel Richard M Higashi Teresa W-M Fan Pankaj Seth 6-Phosphogluconate dehydrogenase (6PGD), a key checkpoint in reprogramming of regulatory T cells metabolism and function eLife regulatory T cell metabolism 6PGD immunoregulation glucose pentose phosphate pathway |
| title | 6-Phosphogluconate dehydrogenase (6PGD), a key checkpoint in reprogramming of regulatory T cells metabolism and function |
| title_full | 6-Phosphogluconate dehydrogenase (6PGD), a key checkpoint in reprogramming of regulatory T cells metabolism and function |
| title_fullStr | 6-Phosphogluconate dehydrogenase (6PGD), a key checkpoint in reprogramming of regulatory T cells metabolism and function |
| title_full_unstemmed | 6-Phosphogluconate dehydrogenase (6PGD), a key checkpoint in reprogramming of regulatory T cells metabolism and function |
| title_short | 6-Phosphogluconate dehydrogenase (6PGD), a key checkpoint in reprogramming of regulatory T cells metabolism and function |
| title_sort | 6 phosphogluconate dehydrogenase 6pgd a key checkpoint in reprogramming of regulatory t cells metabolism and function |
| topic | regulatory T cell metabolism 6PGD immunoregulation glucose pentose phosphate pathway |
| url | https://elifesciences.org/articles/67476 |
| work_keys_str_mv | AT saeeddaneshmandi 6phosphogluconatedehydrogenase6pgdakeycheckpointinreprogrammingofregulatorytcellsmetabolismandfunction AT teresacassel 6phosphogluconatedehydrogenase6pgdakeycheckpointinreprogrammingofregulatorytcellsmetabolismandfunction AT richardmhigashi 6phosphogluconatedehydrogenase6pgdakeycheckpointinreprogrammingofregulatorytcellsmetabolismandfunction AT teresawmfan 6phosphogluconatedehydrogenase6pgdakeycheckpointinreprogrammingofregulatorytcellsmetabolismandfunction AT pankajseth 6phosphogluconatedehydrogenase6pgdakeycheckpointinreprogrammingofregulatorytcellsmetabolismandfunction |