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Long-term antigen exposure irreversibly modifies metabolic requirements for T cell function.

ABSTRACT: Energy metabolism is essential for T cell function. However, how persistent antigenic stimulation affects T cell metabolism is unknown. Here, we report that long-term in vivo antigenic exposure induced a specific deficit in numerous metabolic enzymes. Accordingly, T cells exhibited low basal glycolytic flux and limited respiratory capacity. Strikingly, blockade of inhibitory receptor PD-1 stimulated the production of IFNγ in chronic T cells, but failed to shift their metabolism towards aerobic glycolysis, as observed in effector T cells. Instead, chronic T cells appeared to rely on oxidative phosphorylation (OXPHOS) and fatty acid oxidation (FAO) to produce ATP for IFNγ synthesis. Check-point blockade, however, increased mitochondrial production of superoxide and reduced viability and effector function. Thus, in the absence of a glycolytic switch, PD-1-mediated inhibition appears essential for limiting oxidative metabolism linked to effector function in chronic T cells, thereby promoting survival and functional fitness.

SUBMITTER: Bettonville M

PROVIDER: S-EPMC6025959 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Long-term antigen exposure irreversibly modifies metabolic requirements for T cell function.

Bettonville Marie M d'Aria Stefania S Weatherly Kathleen K Porporato Paolo E PE Zhang Jinyu J Bousbata Sabrina S Sonveaux Pierre P Braun Michel Y MY

eLife 20180618

Energy metabolism is essential for T cell function. However, how persistent antigenic stimulation affects T cell metabolism is unknown. Here, we report that long-term in vivo antigenic exposure induced a specific deficit in numerous metabolic enzymes. Accordingly, T cells exhibited low basal glycolytic flux and limited respiratory capacity. Strikingly, blockade of inhibitory receptor PD-1 stimulated the production of IFNγ in chronic T cells, but failed to shift their metabolism towards aerobic g ...[more]

PMID: 29911570

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Long-term antigen exposure irreversibly modifies metabolic requirements for T cell function.

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Long-term antigen exposure irreversibly modifies metabolic requirements for T cell function.

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