Non-oxidative pentose phosphate pathway controls regulatory T cell function by integrating metabolism and epigenetics.
Nat Metab
; 4(5): 559-574, 2022 05.
Article
en En
| MEDLINE
| ID: mdl-35606596
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.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Vía de Pentosa Fosfato
/
Transcetolasa
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Autoinmunidad
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Linfocitos T Reguladores
Límite:
Animals
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Humans
Idioma:
En
Revista:
Nat Metab
Año:
2022
Tipo del documento:
Article
País de afiliación:
China