Immunological Disorders: Regulation of Ca²⁺ Signaling in T Lymphocytes

Engagement of T cell receptors (TCRs) with cognate antigens triggers cascades of signaling pathways in helper T cells. TCR signaling is essential for the effector function of helper T cells including proliferation, differentiation, and cytokine production. It also modulates effector T cell fate by inducing cell death, anergy (nonresponsiveness), exhaustion, and generation of regulatory T cells. One of the main axes of TCR signaling is the Ca²⁺-calcineurin-nuclear factor of activated T cells (NFAT) signaling pathway. Stimulation of TCRs triggers depletion of intracellular Ca²⁺ store and, in turn, activates store-operated Ca²⁺ entry (SOCE) to raise the intracellular Ca²⁺ concentration. SOCE in T cells is mediated by the Ca²⁺ release-activated Ca²⁺ (CRAC) channels, which have been very well characterized in terms of their electrophysiological properties. Identification of STIM1 as a sensor to detect depletion of the endoplasmic reticulum (ER) Ca²⁺ store and Orai1 as the pore subunit of CRAC channels has dramatically advanced our understanding of the regulatory mechanism of Ca²⁺ signaling in T cells. In this review, we discuss our current understanding of Ca²⁺ signaling in T cells with specific focus on the mechanism of CRAC channel activation and regulation via protein interactions. In addition, we will discuss the role of CRAC channels in effector T cells, based on the analyses of genetically modified animal models.