Calcium-dependent activation of T-lymphocytes (original) (raw)
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Frontiers in immunology, 2013
the potential involvement of Ca v 1.4 in non-excitable cells as mast cells (McRory et al., 2004) and more recently in mouse T-lymphocytes (Omilusik et al., 2011). CalCium in T-lymphoCyTes: prominenT role of The sTim-orai paThway In T-lymphocytes, Ca 2+ ions are important for the activation of many enzymes including phospholipase C gamma (PLCγ), classical protein kinases C, for proper protein folding, for the accessibility of key enzymes in T-cell transduction, and as a second messenger (Vig and Kinet, 2009). Variations in the intracellular calcium concentration ([Ca] i) are responsible for modulating the transcription of more than 75% of genes induced or down-regulated by T-cell receptor engagement in T-lymphocytes (Feske et al., 2001). The intracellular [Ca] i that decides the cellular fate is tightly regulated in both resting and activated conditions. The calcium concentration in the external medium is about 1-2 mM, whereas the [Ca] i is about 50-100 nM and depends on the calcium channels expressed at both the cell and endoplasmic reticulum (ER) membranes, on exchangers, pumps, … Activation of potassium channels that extrude the potassium from the cell is needed for supporting the electrochemical driving force allowing the calcium influx. In T-lymphocytes, TCR engagement results in a cascade of tyrosine kinase activation, the constitution of a platform transducing the signal with the recruitment of adapters and enzymes such as PLCγ that generates inositol trisphosphate (IP3) and diacylglycerol. IP3 binds to its receptors on the ER membrane leading to the release of ER Ca 2+ stores, which induces a conformational change of STIM1, an ER Ca 2+ sensor. STIM1 then localizes near the cell membrane, and activates the SOCC
Ca2+ signals and T lymphocytes “New mechanisms and functions in Ca2+ signalling”
Biology of the Cell, 2004
Interaction between a T cell and an antigen-presenting cell leads to the rapid formation of an immunological synapse allowing antigen detection by the T cell and the development of an immune response. Antigen detection triggers various cellular responses including a modest but sustained T cell Ca 2+ increase. In this review are discussed a series of related questions. What are the various molecular events by which a T cell Ca 2+ response can be triggered in the immunological synapse by a very small amount of antigen ? How is Ca 2+ released from intracellular stores and how can these stores remain empty for hours ? Through which channels does Ca 2+ influx takes place, and how is Ca 2+ influx coupled to Ca 2+ release from intracellular stores ? What are the main immediate and indirect cellular targets of the Ca 2+ increase ?
The Journal of Cell Biology, 2000
Although the crucial role of Ca2+ influx in lymphocyte activation has been well documented, little is known about the properties or expression levels of Ca2+ channels in normal human T lymphocytes. The use of Na+ as the permeant ion in divalent-free solution permitted Ca2+ release-activated Ca2+ (CRAC) channel activation, kinetic properties, and functional expression levels to be investigated with single channel resolution in resting and phytohemagglutinin (PHA)-activated human T cells. Passive Ca2+ store depletion resulted in the opening of 41-pS CRAC channels characterized by high open probabilities, voltage-dependent block by extracellular Ca2+ in the micromolar range, selective Ca2+ permeation in the millimolar range, and inactivation that depended upon intracellular Mg2+ ions. The number of CRAC channels per cell increased greatly from ∼15 in resting T cells to ∼140 in activated T cells. Treatment with the phorbol ester PMA also increased CRAC channel expression to ∼60 channels...
Singularities of calcium signaling in effector T-lymphocytes
Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, 2013
Intracellular calcium concentration Ca v 1 calcium channels CD4 + helper T (Th) lymphocytes orchestrate the immune response and include several types of effectors such as Th1, Th17 and Th2 cells. They fight against intracellular, extracellular pathogens and parasites respectively. They may also cause distinct immunopathological disorders. Th1 and Th17 are implicated in the development of autoimmune diseases while Th2 cells can initiate allergic diseases. These subsets differ by their TCR-associated signaling. In addition, the regulation of intracellular calcium concentration is not the same in Th1, Th2 and 17 cells. Our group showed that Th2 cells selectively overexpressed voltage-activated calcium (Ca v 1)-related channels. An increasing number of groups report the presence of Ca v 1-related products in T-lymphocyte subsets. This is a matter of debate since these calcium channels are classically defined as activated by high cell membrane depolarization in excitable cells. However, the use of mice with ablation of some Ca v 1 subunits shows undoubtedly an immune phenotype raising the question of how Ca v 1 channels are regulated in lymphocytes. We showed that knocking down Ca v 1.2 and/or Ca v 1.3 subunits impairs the functions of Th2 lymphocytes and is beneficial in experimental models of asthma, while it has no effect on Th1 cell functions. Beyond the role of Ca v 1 channels in T-lymphocytes, the identification of key components selectively implicated in one or the other T cell subset paves the way for the design of new selective therapeutic targets in the treatment of immune disorders while preserving the other T-cell subsets. This article is part of a Special Issue entitled: 12th European Symposium on Calcium.
Immunity, 2011
The transport of calcium ions (Ca(2+)) to the cytosol is essential for immunoreceptor signaling, regulating lymphocyte differentiation, activation, and effector function. Increases in cytosolic-free Ca(2+) concentrations are thought to be mediated through two interconnected and complementary mechanisms: the release of endoplasmic reticulum Ca(2+) "stores" and "store-operated" Ca(2+) entry via plasma membrane channels. However, the identity of molecular components conducting Ca(2+) currents within developing and mature T cells is unclear. Here, we have demonstrated that the L-type "voltage-dependent" Ca(2+) channel Ca(V)1.4 plays a cell-intrinsic role in the function, development, and survival of naive T cells. Plasma membrane Ca(V)1.4 was found to be essential for modulation of intracellular Ca(2+) stores and T cell receptor (TCR)-induced rises in cytosolic-free Ca(2+), impacting activation of Ras-extracellular signal-regulated kinase (ERK) and nuclear ...
Nature Immunology, 2009
Survival of T lymphocytes requires sustained Ca 2+ influx-dependent gene expression. The molecular mechanism, which governs sustained Ca 2+ influx in naive T lymphocytes, is unknown. Here we report an essential role for the β3 regulatory subunit of Ca v channels in the maintenance of naive CD8 + T cells. β3 deficiency resulted in a profound survival defect of CD8 + T cells. This defect correlated with depletion of the pore-forming subunit Ca v 1.4 and attenuation of T cell receptor-mediated global Ca 2+ entry in the absence of β3 in CD8 + T cells. Ca v 1.4 and β3 associated with T cell signaling machinery and Ca v 1.4 localized in lipid rafts. Our data demonstrate a mechanism by which Ca 2+ entry is controlled by a Ca v 1.4-β3 channel complex in T cells. Keywords Calcium; Cacnb3; T lymphocyte; Ca v channel; Apoptosis Calcium (Ca 2+) signaling plays a pivotal role in adaptive immune responses. Sustained Ca 2+ influx across the plasma membrane of T cell leads to the activation of NFAT transcription factors. NFATs regulate survival, activation, proliferation and effector functions of T lymphocytes1-4. Despite the established role of Ca 2+ in T lymphocyte development and functions, the mechanism of sustained Ca 2+ entry in naive T lymphocytes remains elusive to date. A well-characterized mode of Ca 2+ entry in T cells is the CRAC (Calcium Release Activated Ca 2+) pathway, in which, two key players, STIM1 and ORAI1 (also known as Correspondence should be addressed to R.A.F.