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Long-term T cell fitness and proliferation is driven by AMPK-dependent regulation of reactive oxygen species

par Lepez, Anouk ;Pirnay, Tiphene ;Denanglaire, Sébastien ;Perez-Morga, David ;Vermeersch, Marjorie ;Leo, Oberdan ;Andris, Fabienne
Référence Scientific reports, 10, 1, page (21673)
Publication Publié, 2020-12-01

Article révisé par les pairs

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Résumé :

The AMP-activated kinase (AMPK) is a major energy sensor metabolic enzyme that is activated early during T cell immune responses but its role in the generation of effector T cells is still controversial. Using both in vitro and in vivo models of T cell proliferation, we show herein that AMPK is dispensable for early TCR signaling and short-term proliferation but required for sustained long-term T cell proliferation and effector/memory T cell survival. In particular, AMPK promoted accumulation of effector/memory T cells in competitive homeostatic proliferation settings. Transplantation of AMPK-deficient hematopoïetic cells into allogeneic host recipients led to a reduced graft-versus-host disease, further bolstering a role for AMPK in the expansion and pathogenicity of effector T cells. Mechanistically, AMPK expression enhances the mitochondrial membrane potential of T cells, limits reactive oxygen species (ROS) production, and resolves ROS-mediated toxicity. Moreover, dampening ROS production alleviates the proliferative defect of AMPK-deficient T cells, therefore indicating a role for an AMPK-mediated ROS control of T cell fitness.