Summary
The transport of calcium ions (Ca2+) to the cytosol is essential for immunoreceptor signaling, regulating lymphocyte differentiation, activation, and effector function. Increases in cytosolic-free Ca2+ concentrations are thought to be mediated through two interconnected and complementary mechanisms: the release of endoplasmic reticulum Ca2+ stores and store-operated Ca2+ entry via plasma membrane channels. However, the identity of molecular components conducting Ca2+ currents within developing and mature Tcells is unclear. Here, we have demonstrated that the L-type voltage-dependent Ca2+ channel CaV1.4 plays a cell-intrinsic role in the function, development, and survival of naive Tcells. Plasma membrane CaV1.4 was found to be essential for modulation of intracellular Ca2+ stores and Tcell receptor (TCR)-induced rises in cytosolic-free Ca2+, impacting activation of Ras-extracellular signal-regulated kinase (ERK) and nuclear factor of activated Tcells (NFAT) pathways. Collectively, these studies revealed that CaV1.4 functions in controlling naive Tcell homeostasis and antigen-driven Tcell immune responses.
CaV1.4 is required for store-operated calcium entry by naive CD4+ and CD8+ Tcells CaV1.4 regulates TCR-induced Ras-ERK and NFAT signaling CaV1.4 modulates the survival of naive CD4+ and CD8+ Tcells Cav1.4 is critical for pathogen-specific CD4+ and CD8+ Tcell responses
Calcium (Ca2+) ions act as universal second messengers in virtually all cell types, including cells of the immune system. In lymphocytes, Ca2+ signals modulate the activation of calcineurin-nuclear factor of activated Tcells (NFAT) and Ras-Mitogen-activated protein kinases (MAPK) pathways, serving to regulate cell activation, proliferation, differentiation, and apoptosis (Oh-hora, 2009andVig and Kinet, 2009). Tcell receptor (TCR) stimulation invokes rises in cytosolic Ca2+ through the activation of phospholipase C-1 (PLC1) and the associated hydrolysis of phosphatidylinositol-3,4-bisphosphate (PIP2) into inositol-1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). Subsequently, IP3 binds IP3 receptors in the endoplasmic reticulum (ER) and induces Ca2+ release from ER storesthus triggering store-operated Ca2+ entry (SOCE) from outside the cell via plasma membrane channels (Oh-hora, 2009andVig and Kinet, 2009). For Ca2+ signaling to affect Tcell fate or effector functions, sustained Ca2+ influx via plasma membrane channels is probably necessary for a number of hours, maintaining cytoplasmic Ca2+ concentrations higher than resting baseline (Oh-hora, 2009).
The identity and number of plasma membrane channels mediating sustained Ca2+ entry into Tcells is unclear (Kotturi etal., 2006). One well-characterized mechanism of entry is through Ca2+ release-activated calcium (CRAC) channels (Oh-hora, 2009). In the CRAC pathway, the Ca2+ sensor STIM1 responds to decreases in ER Ca2+ stores by associating with the CRAC channel pore subunit ORAI1 and activating SOCE. However, loss of ORAI1 in naive Tcells has been found to have minimal effects on their ability to flux Ca2+ or proliferate upon TCR stimulation (Gwack etal., 2008andVig etal., 2008). Other candidate plasma membrane Ca2+ channels operating in lymphocytes include the P2X receptor, transient receptor potential (TRP) cation channels, TRP vanilloid channels, TRP melastatin channels, and voltage-dependent Ca2+ channels (VDCC). It is unknown whether the repertoire of Ca2+ channels operating in Tcells remains constant or changes during various stages of development or differentiation.
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