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 T cell 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 T cell proliferation. We here report that SOCE and calcineurin regulate cell cycle entry of quiescent T cells by controlling glycolysis and oxidative phosphorylation. SOCE directs 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.

Keywords: GLUT1; GLUT3; NFAT; ORAI1; SOCE; STIM1; STIM2; calcineurin; calcium; cell cycle; glycolysis; metabolism; mitochondria.