Suppression of Glut1 and Glucose Metabolism by Decreased Akt/mTORC1 Signaling Drives T Cell Impairment in B Cell Leukemia.
J Immunol
; 197(6): 2532-40, 2016 09 15.
Article
em En
| MEDLINE
| ID: mdl-27511728
ABSTRACT
Leukemia can promote T cell dysfunction and exhaustion that contributes to increased susceptibility to infection and mortality. The treatment-independent mechanisms that mediate leukemia-associated T cell impairments are poorly understood, but metabolism tightly regulates T cell function and may contribute. In this study, we show that B cell leukemia causes T cells to become activated and hyporesponsive with increased PD-1 and TIM3 expression similar to exhausted T cells and that T cells from leukemic hosts become metabolically impaired. Metabolic defects included reduced Akt/mammalian target of rapamycin complex 1 (mTORC1) signaling, decreased expression of the glucose transporter Glut1 and hexokinase 2, and reduced glucose uptake. These metabolic changes correlated with increased regulatory T cell frequency and expression of PD-L1 and Gal-9 on both leukemic and stromal cells in the leukemic microenvironment. PD-1, however, was not sufficient to drive T cell impairment, as in vivo and in vitro anti-PD-1 blockade on its own only modestly improved T cell function. Importantly, impaired T cell metabolism directly contributed to dysfunction, as a rescue of T cell metabolism by genetically increasing Akt/mTORC1 signaling or expression of Glut1 partially restored T cell function. Enforced Akt/mTORC1 signaling also decreased expression of inhibitory receptors TIM3 and PD-1, as well as partially improved antileukemia immunity. Similar findings were obtained in T cells from patients with acute or chronic B cell leukemia, which were also metabolically exhausted and had defective Akt/mTORC1 signaling, reduced expression of Glut1 and hexokinase 2, and decreased glucose metabolism. Thus, B cell leukemia-induced inhibition of T cell Akt/mTORC1 signaling and glucose metabolism drives T cell dysfunction.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Linfócitos T
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Leucemia Linfocítica Crônica de Células B
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Transdução de Sinais
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Complexos Multiproteicos
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Proteínas Proto-Oncogênicas c-akt
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Transportador de Glucose Tipo 1
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Serina-Treonina Quinases TOR
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Glucose
Limite:
Animals
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Humans
Idioma:
En
Revista:
J Immunol
Ano de publicação:
2016
Tipo de documento:
Article