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

Publication date: Available online 11 October 2017
Source:Immunity
Author(s): Martin Vaeth, Mate Maus, Stefan Klein-Hessling, Elizaveta Freinkman, Jun Yang, Miriam Eckstein, Scott Cameron, Stuart E. Turvey, Edgar Serfling, Friederike Berberich-Siebelt, Richard Possemato, Stefan Feske
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.

Graphical abstract

Teaser

Clonal expansion of T cells is critical for protective immunity. Vaeth et al. (2017) demonstrate that store-operated calcium entry (SOCE), calcineurin, and NFAT control cell-cycle entry and proliferation of activated T cells through upregulation of glycolysis and oxidative phosphorylation.


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