Store-Operated Ca

Store-operated Ca2+ entry (SOCE) is the main Ca2+ influx pathway in lymphocytes and essential for T cell function and adaptive immunity. SOCE is mediated by Ca2+ release-activated Ca2+ (CRAC) channels that are activated by stromal interaction molecules (STIM) 1 and STIM2. SOCE regulates many Ca2+-dependent signaling molecules including calcineurin and inhibition of SOCE or calcineurin impairs antigen-dependent T cell proliferation. We here report that SOCE and calcineurin regulated cell cycle entry of quiescent T cells by controlling glycolysis and oxidative phosphorylation. SOCE directed the metabolic reprogramming of naive T cells by regulating the expression of glucose transporters, glycolytic enzymes and metabolic regulators through the activation of nuclear factor of activated T cells (NFAT) and the PI3K-AKT kinase-mTOR nutrient sensing pathway. We propose that SOCE controls a critical ‘metabolic checkpoint’ at which T cells assess adequate nutrient supply to support clonal expansion and adaptive immune responses.