Store-Operated Ca2+ Entry Controls Clonal Expansion of T Cells through Metabolic Reprogramming

Abstract

Store-operated Ca2+ entry (SOCE) is the main Ca2+ influx pathway in lymphocytes and is essential for Tcell function and adaptive immunity. SOCE is mediated by Ca2+ release-activated Ca2+ (CRAC) channels that are activated by stromal interaction molecule (STIM) 1 and STIM2. SOCE regulates many Ca2+-dependent signaling molecules, including calcineurin, and inhibition of SOCE or calcineurin impairs antigen-dependent Tcell proliferation. We here report that SOCE and calcineurin regulate cell cycle entry of quiescent Tcells by controlling glycolysis and oxidative phosphorylation. SOCE directs the metabolic reprogramming of naive Tcells by regulating the expression of glucose transporters, glycolytic enzymes, and metabolic regulators through the activation of nuclear factor of activated Tcells (NFAT) and the PI3K-AKT kinase-mTOR nutrient-sensing pathway. We propose that SOCE controls a critical "metabolic checkpoint" at which Tcells assess adequate nutrient supply to support clonal expansion and adaptive immune responses.