Pole of Pharmacology & Therapeutics, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Brussels, Belgium
Jinyu Zhang
Institute for Medical Immunology, Université Libre de Bruxelles, Gosselies, Belgium
Sabrina Bousbata
Laboratory of Molecular Parasitology, Proteomic Platform, Institute of Molecular Biology and Medicine, Université Libre de Bruxelles, Gosselies, Belgium
Pierre Sonveaux
Pole of Pharmacology & Therapeutics, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Brussels, Belgium
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.
