In cells of the immune system, calcium signals are essential for diverse cellular functions including differentiation, effector function, and gene transcription. After the engagement of immunoreceptors such as T-cell and B-cell antigen receptors and the Fc receptors on mast cells and NK cells, the intracellular concentration of calcium ions is increased through the sequential operation of two interdependent processes: depletion of endoplasmic reticulum Ca2+ stores as a result of binding of inositol trisphosphate (IP3) to IP3 receptors, followed by 'store-operated' Ca2+ entry through plasma membrane Ca2+ channels. In lymphocytes, mast cells and other immune cell types, store-operated Ca2+ entry through specialized Ca2+ release-activated calcium (CRAC) channels constitutes the major pathway of intracellular Ca2+ increase. A recent breakthrough in our understanding of CRAC channel function is the identification of stromal interaction molecule (STIM) and ORAI, two essential regulators of CRAC channel function. This review focuses on the signaling pathways upstream and downstream of Ca2+ influx (the STIM/ORAI and calcineurin/NFAT pathways, respectively). Introduction: Calcium (Ca2+) is a universal second messenger with a pivotal role in almost all cell types [1,2••,3••]. In cells of the immune system, including T cells, B cells, mast cells, and many other cell types, Ca2+ signals control proliferation, differentiation, apoptosis, and a variety of transcriptional programs [4,5••,6••]. The consequences of Ca2+ signals can be distinguished by whether short-term or long-term functions are affected. Short-term functions are generally influenced within minutes and are independent of new gene expression. They include the regulation of lymphocyte motility and the degranulation of allergen-sensitized mast cells or cytolytic CD8+ T cells [7-10]. The interaction of T cells with antigen-presenting cells (APCs) bearing antigenic peptides induces a quick increase of cytoplasmic Ca2+ concentration, which stops the movement of T cells and allows them to form stable immunological synapses, a process that is crucial for long-term function. Under conditions where high-affinity antigenic peptides and costimulatory signals are absent, T cells make only brief engagements with APC and display weak and infrequent Ca2+ spikes . The long-term functions downstream of Ca2+ signaling include lymphocyte proliferation, expression of activation-associated genes, effector functions such as the production of cytokines and chemokines, the differentiation of naïve T cells into various effector or memory T cells, and the establishment - in the absence of costimulation - of an antigen-unresponsive state known as anergy . These events all need sustained Ca2+ influx to keep cytoplasmic Ca2+ concentrations at higher than basal levels for several hours.
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