Calcium (Ca2+) signalling is of paramount importance to immunity. Regulated increases in cytosolic and organellar Ca2+ concentrations in lymphocytes control complex and crucial effector functions such as metabolism, proliferation, differentiation, antibody and cytokine secretion and cytotoxicity. Altered Ca2+ regulation in lymphocytes leads to various autoimmune, inflammatory and immunodeficiency syndromes. Several types of plasma membrane and organellar Ca2+-permeable channels are functional in T cells. They contribute highly localized spatial and temporal Ca2+ microdomains that are required for achieving functional specificity. While the mechanistic details of these Ca2+ microdomains are only beginning to emerge, it is evident that through crosstalk, synergy and feedback mechanisms, they fine-tune T cell signalling to match complex immune responses. In this article, we review the expression and function of various Ca2+-permeable channels in the plasma membrane, endoplasmic reticulum, mitochondria and endolysosomes of T cells and their role in shaping immunity and the pathogenesis of immune-mediated diseases.
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Research in the authors’ laboratories is supported by grants R01HL123364, R01HL097111 and R21AG050072 from the US National Institutes of Health and grant NPRP8-110-3-021 from the Qatar National Research Fund (QNRF) to M.T.
Nature Reviews Immunology thanks S. Feske and other anonymous reviewer(s) for their contribution to the peer review of this work.
The authors declare no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
- Membrane potential
(Vm). The difference in electric potential between the interior and the exterior of a biological membrane. In resting T cells, the plasma membrane potential is typically between −60 and −50 mV.
- Ion channels
Transmembrane proteins that form oligomers around a central pore, which allows specific ions to flow across biological membranes. Channels conduct ions according to the electrochemical gradient of this membrane and, therefore, this process does not consume energy in the form of ATP.
- Voltage-activated Ca2+ channels
(CaV channels). Ca2+ selective channels located at the plasma membrane (PM) of excitable cells, such as muscle cells and neurons, and activated in response to PM depolarization. In T cells, CaV channels might be activated by voltage-dependent or voltage-independent means.
- Inositol-1,4,5-trisphosphate receptors
(InsP3Rs). Ca2+ release channels present in the endoplasmic reticulum (ER) membrane that release Ca2+ from the ER lumen to the cytosol in response to allosteric binding of Ca2+ and inositol-1,4,5-triphosphate.
- Ryanodine receptors
(RYRs). Ca2+ release channels present in the endoplasmic reticulum (ER) membrane that mediate release of Ca2+ from the ER lumen to the cytosol on activation by Ca2+, nicotinic acid adenine dinucleotide phosphate (NAADP) and cyclic ADP-ribose (cADPR).
- Ca2+ microdomains
Discrete sites in the cytosol localized near (within a few nanometres) the mouth of Ca2+ channels of either the plasma membrane or organellar membranes. These regions, which contain high Ca2+ concentrations, are the sites where specific Ca2+-activated effector proteins are located. Ca2+ microdomains near specific Ca2+ channels are the major means by which the ubiquitous Ca2+ ion ensures specificity of signal transduction.
- Mitochondrial Ca2+ uniporter
(MCU). A mitochondrial Ca2+ selective channel complex located in the inner mitochondrial membrane that conducts Ca2+ from the cytosol to the mitochondrial matrix.
- Ion pumps
Transmembrane proteins that transport ions against the electrochemical gradient of a membrane, and this function requires energy in the form of ATP hydrolysis. Examples include sarcoplasmic/endoplasmic reticulum Ca2+ ATPase (SERCA), which pumps Ca2+ from the cytosol into the endoplasmic reticulum; and plasma membrane Ca2+ ATPase (PMCA), which pumps Ca2+ from the cytosol to the extracellular space.
- Two pore channels
(TPCs). Ion channels located in the membrane of endolysosomes that are proposed to release Ca2+ and Na+ from endolysosomes to the cytosol and are activated by nicotinic acid adenine dinucleotide phosphate (NAADP) and by phosphoinositide species localized in the endolysosomal membrane, such as phosphatidylinositol-3,5-bisphosphate.
- Transient receptor potential mucolipin channels
(TRPML channels). Non-selective cation channels located on the surface of endolysosomes that release Ca2+ and Na+ from these organelles into the cytosol. TRPML channels are activated by phosphoinositide species localized in the endolysosomal membrane, such as phosphatidylinositol-3,5-bisphosphate.
- Store-operated Ca2+ entry
(SOCE). The most ubiquitous Ca2+ influx pathway in non-excitable cells, which is activated when endoplasmic reticulum Ca2+ stores are depleted. It is mediated by plasma membrane ORAI Ca2+ channels activated by direct binding of stromal interaction molecule (STIM) proteins.
- Ca2+ release-activated Ca2+
(CRAC). The biophysical manifestation of store-operated Ca2+ entry and ORAI channels measured by whole-cell patch clamp electrophysiology. CRAC currents are highly Ca2+ selective.
- Immune synapse
The nanoscale interface of interaction between a lymphocyte and an antigen-presenting cell.
- Nuclear factor of activated T cells
(NFAT). An important family of transcription factors that are Ca2+ activated. Ca2+–calmodulin activates the phosphatase calcineurin, which then dephosphorylates NFAT, causing its import into the nucleus to mediate gene transcription of many cytokines, transcription factors and metabolic genes.
- Patch clamp electrophysiology
A laboratory technique used to measure ionic currents through specific channels from single living cells or from a patch of cell membrane. Under the voltage clamp configuration, controlled (clamped) voltage values are applied to the cell membrane by the experimenter, and the resulting currents are measured.
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Trebak, M., Kinet, JP. Calcium signalling in T cells. Nat Rev Immunol 19, 154–169 (2019). https://doi.org/10.1038/s41577-018-0110-7
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