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 αβ⁺ 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.