Nat Metab. co-auth.: group Thorens

The glucose transporter 2 regulates CD8+ T cell function via environment sensing

Hongmei Fu # 1Juho Vuononvirta # 1Silvia Fanti 1Fabrizia Bonacina 2Antonio D’Amati 3Guosu Wang 1Thanushiyan Poobalasingam 1Maria Fankhaenel 4Davide Lucchesi 1Rachel Coleby 1David Tarussio 5Bernard Thorens 5Robert J Hearnden 4M Paula Longhi 1Paul Grevitt 4Madeeha H Sheikh 1Egle Solito 1Susana A Godinho 4Michele Bombardieri 1David M Smith 6Dianne Cooper 1Asif J Iqbal 7Jeffrey C Rathmell 8Samuel Schaefer 8Valle Morales 4Katiuscia Bianchi 4Giuseppe Danilo Norata 2Federica M Marelli-Berg 9

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T cell activation is associated with a profound and rapid metabolic response to meet increased energy demands for cell division, differentiation and development of effector function. Glucose uptake and engagement of the glycolytic pathway are major checkpoints for this event. Here we show that the low-affinity, concentration-dependent glucose transporter 2 (Glut2) regulates the development of CD8+ T cell effector responses in mice by promoting glucose uptake, glycolysis and glucose storage. Expression of Glut2 is modulated by environmental factors including glucose and oxygen availability and extracellular acidification. Glut2 is highly expressed by circulating, recently primed T cells, allowing efficient glucose uptake and storage. In glucose-deprived inflammatory environments, Glut2 becomes downregulated, thus preventing passive loss of intracellular glucose. Mechanistically, Glut2 expression is regulated by a combination of molecular interactions involving hypoxia-inducible factor-1 alpha, galectin-9 and stomatin. Finally, we show that human T cells also rely on this glucose transporter, thus providing a potential target for therapeutic immunomodulation.