Calcium signaling in the development and function of T-lineage cells

Ca2+ signals are essential for diverse cellular functions including differentiation, effector function, and gene transcription in the immune system. In lymphocytes, sustained Ca2+ entry is necessary for complete and long-lasting activation of calcineurin/nuclear factor of activated T cells (NFAT) pathways. Engagement of immunoreceptors, such as the T-cell antigen receptor, induces store-operated Ca2+ entry (SOCE) through plasma membrane Ca2+ channels. In lymphocytes, mast cells, and other immune cell types, SOCE through highly Ca2+-selective Ca2+ release-activated Ca2+ (CRAC) channels constitute the major pathway of intracellular Ca2+ increase. A recent breakthrough in our understanding of CRAC channel function is the identification of STIM and ORAI, two essential regulators of CRAC channel function. This discovery allows us to directly address the physiological role of Ca2+ entry in lymphocytes. A growing number of studies have emphasized that Ca2+/calcineurin/NFAT pathway is crucial for both development and function of all T-cell lineage cells, such as conventional alphabeta+ TCR T cells, Foxp3+ regulatory T cells, and invariant natural killer T cells. This review focuses on the role of the signaling pathways upstream and downstream of Ca2+ influx in the development and function in T-cell lineages.