Lactate dehydrogenase inhibition synergizes with IL-21 to promote CD8⁺ T cell stemness and antitumor immunity.

ABSTRACT: Interleukin (IL)-2 and IL-21 dichotomously shape CD8⁺ T cell differentiation. IL-2 drives terminal differentiation, generating cells that are poorly effective against tumors, whereas IL-21 promotes stem cell memory T cells (T_SCM) and antitumor responses. Here we investigated the role of metabolic programming in the developmental differences induced by these cytokines. IL-2 promoted effector-like metabolism and aerobic glycolysis, robustly inducing lactate dehydrogenase (LDH) and lactate production, whereas IL-21 maintained a metabolically quiescent state dependent on oxidative phosphorylation. LDH inhibition rewired IL-2-induced effects, promoting pyruvate entry into the tricarboxylic acid cycle and inhibiting terminal effector and exhaustion programs, including mRNA

SUBMITTER: Hermans D 

PROVIDER: S-EPMC7084161 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature