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.
Subscribe to Journal
Get full journal access for 1 year
only $22.08 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Vig, M. & Kinet, J. P. Calcium signaling in immune cells. Nat. Immunol. 10, 21–27 (2009).
Cai, X., Wang, X., Patel, S. & Clapham, D. E. Insights into the early evolution of animal calcium signaling machinery: a unicellular point of view. Cell Calcium 57, 166–173 (2015).
Hogan, P. G., Lewis, R. S. & Rao, A. Molecular basis of calcium signaling in lymphocytes: STIM and ORAI. Annu. Rev. Immunol. 28, 491–533 (2010).
Feske, S., Wulff, H. & Skolnik, E. Y. Ion channels in innate and adaptive immunity. Annu. Rev. Immunol. 33, 291–353 (2015).
Feske, S., Skolnik, E. Y. & Prakriya, M. Ion channels and transporters in lymphocyte function and immunity. Nat. Rev. Immunol. 12, 532–547 (2012).
Berridge, M. J. The inositol trisphosphate/calcium signaling pathway in health and disease. Physiol. Rev. 96, 1261–1296 (2016). This paper provides an excellent and comprehensive review on Ins(1,4,5)P 3 signalling pathways in health and disease.
De Stefani, D., Rizzuto, R. & Pozzan, T. Enjoy the trip: calcium in mitochondria back and forth. Annu. Rev. Biochem. 85, 161–192 (2016). This is an excellent review on mitochondrial Ca 2+ signalling and its role in shaping cell signalling and cell function.
Foskett, J. K., White, C., Cheung, K. H. & Mak, D. O. Inositol trisphosphate receptor Ca2+ release channels. Physiol. Rev. 87, 593–658 (2007).
Raffaello, A., Mammucari, C., Gherardi, G. & Rizzuto, R. Calcium at the center of cell signaling: interplay between endoplasmic reticulum, mitochondria, and lysosomes. Trends Biochem. Sci. 41, 1035–1049 (2016).
Xiong, J. & Zhu, M. X. Regulation of lysosomal ion homeostasis by channels and transporters. Sci. China Life Sci. 59, 777–791 (2016). This review provides an excellent introduction to ion channel networks in lysosomes and their role in lysosomal function.
Cahalan, M. D. & Chandy, K. G. The functional network of ion channels in T lymphocytes. Immunol. Rev. 231, 59–87 (2009). References 4 and 11 are detailed review articles that provide excellent overviews of different ions and ion channels and their role in controlling innate and adaptive immunity.
Badou, A. et al. Critical role for the β regulatory subunits of Cav channels in T lymphocyte function. Proc. Natl Acad. Sci. USA 103, 15529–15534 (2006).
Omilusik, K. et al. The Ca(v)1.4 calcium channel is a critical regulator of T cell receptor signaling and naive T cell homeostasis. Immunity 35, 349–360 (2011).
Wang, H. et al. Low-voltage-activated CaV3.1 calcium channels shape T helper cell cytokine profiles. Immunity 44, 782–794 (2016). This article provides the first patch clamp evidence of T-type Ca 2+ channels in T cells and their role in cytokine production and immune function.
Parker, I. & Smith, I. F. Recording single-channel activity of inositol trisphosphate receptors in intact cells with a microscope, not a patch clamp. J. Gen. Physiol. 136, 119–127 (2010).
Mikoshiba, K. IP3 receptor/Ca2+ channel: from discovery to new signaling concepts. J. Neurochem. 102, 1426–1446 (2007).
Guse, A. H. & Wolf, I. M. Ca2+ microdomains, NAADP and type 1 ryanodine receptor in cell activation. Biochim. Biophys. Acta 1863, 1379–1384 (2016).
Baughman, J. M. et al. Integrative genomics identifies MCU as an essential component of the mitochondrial calcium uniporter. Nature 476, 341–345 (2011).
De Stefani, D., Raffaello, A., Teardo, E., Szabo, I. & Rizzuto, R. A forty-kilodalton protein of the inner membrane is the mitochondrial calcium uniporter. Nature 476, 336–340 (2011). References 18 and 19 were the first to identify the MCU, which is largely responsible for Ca 2+ uptake by mitochondria.
McCormack, J. G. & Denton, R. M. The effects of calcium ions and adenine nucleotides on the activity of pig heart 2-oxoglutarate dehydrogenase complex. Biochem. J. 180, 533–544 (1979).
Denton, R. M. & McCormack, J. G. Ca2+ as a second messenger within mitochondria of the heart and other tissues. Annu. Rev. Physiol. 52, 451–466 (1990).
McCormack, J. G., Halestrap, A. P. & Denton, R. M. Role of calcium ions in regulation of mammalian intramitochondrial metabolism. Physiol. Rev. 70, 391–425 (1990).
Hansford, R. G. Physiological role of mitochondrial Ca2+ transport. J. Bioenerg. Biomembr. 26, 495–508 (1994).
Montero, M. et al. Chromaffin-cell stimulation triggers fast millimolar mitochondrial Ca2+ transients that modulate secretion. Nat. Cell Biol. 2, 57–61 (2000).
Cali, T., Brini, M. & Carafoli, E. Regulation of cell calcium and role of plasma membrane calcium ATPases. Int. Rev. Cell. Mol. Biol. 332, 259–296 (2017).
Stafford, N., Wilson, C., Oceandy, D., Neyses, L. & Cartwright, E. J. The plasma membrane calcium ATPases and their role as major new players in human disease. Physiol. Rev. 97, 1089–1125 (2017).
Chemaly, E. R., Troncone, L. & Lebeche, D. SERCA control of cell death and survival. Cell Calcium 69, 46–61 (2018).
Wu, K. D., Lee, W. S., Wey, J., Bungard, D. & Lytton, J. Localization and quantification of endoplasmic reticulum Ca2+-ATPase isoform transcripts. Am. J. Physiol. 269, C775–C784 (1995).
Chen, J. et al. CD22 attenuates calcium signaling by potentiating plasma membrane calcium-ATPase activity. Nat. Immunol. 5, 651–657 (2004).
Palty, R. et al. NCLX is an essential component of mitochondrial Na+/Ca2+ exchange. Proc. Natl Acad. Sci. USA 107, 436–441 (2010). This paper is the first to identify the molecular identity of the Na + /Ca 2+ exchanger in mitochondria (NCLX), which is responsible for Ca 2+ extrusion from mitochondria.
Nissim, B.-K. T. et al. Mitochondria control store-operated Ca2+ entry through Na+ and redox signals. EMBO J. 36, 797–815 (2017).
Sekler, I. Standing of giants shoulders the story of the mitochondrial Na+Ca2+ exchanger. Biochem. Biophys. Res. Commun. 460, 50–52 (2015).
Xu, H. & Ren, D. Lysosomal physiology. Annu. Rev. Physiol. 77, 57–80 (2015).
Paroutis, P., Touret, N. & Grinstein, S. The pH of the secretory pathway: measurement, determinants, and regulation. Physiology (Bethesda) 19, 207–215 (2004).
Christensen, K. A., Myers, J. T. & Swanson, J. A. pH-dependent regulation of lysosomal calcium in macrophages. J. Cell Sci. 115, 599–607 (2002).
Morgan, A. J., Davis, L. C., Ruas, M. & Galione, A. TPC: the NAADP discovery channel? Biochem. Soc. Trans. 43, 384–389 (2015).
Morgan, A. J., Platt, F. M., Lloyd-Evans, E. & Galione, A. Molecular mechanisms of endolysosomal Ca2+ signalling in health and disease. Biochem. J. 439, 349–374 (2011).
Courtney, A. H., Lo, W. L. & Weiss, A. TCR signaling: mechanisms of initiation and propagation. Trends Biochem. Sci. 43, 108–123 (2018).
Putney, J. W. Jr. A model for receptor-regulated calcium entry. Cell Calcium 7, 1–12 (1986).
Putney, J. W. Jr. Capacitative calcium entry revisited. Cell Calcium 11, 611–624 (1990).
Takemura, H., Hughes, A. R., Thastrup, O. & Putney, J. W. Jr. Activation of calcium entry by the tumor promoter thapsigargin in parotid acinar cells. Evidence that an intracellular calcium pool and not an inositol phosphate regulates calcium fluxes at the plasma membrane. J. Biol. Chem. 264, 12266–12271 (1989).
Hoth, M. & Penner, R. Depletion of intracellular calcium stores activates a calcium current in mast cells. Nature 355, 353–356 (1992).
Prakriya, M. & Lewis, R. S. Store-operated calcium channels. Physiol. Rev. 95, 1383–1436 (2015). This is an exhaustive review that provides an outstanding overview of store-operated Ca 2+ channels, including their biophysical properties, activation, regulation and cellular function.
Trebak, M. & Putney, J. W. Jr. ORAI calcium channels. Physiology (Bethesda) 32, 332–342 (2017). This review provides a brief historical overview of store-operated Ca 2 + channels and a summary of the various native Ca 2 + channels encoded by ORAI proteins.
Liou, J. et al. STIM is a Ca2+ sensor essential for Ca2+-store-depletion-triggered Ca2+ influx. Curr. Biol. 15, 1235–1241 (2005).
Roos, J. et al. STIM1, an essential and conserved component of store-operated Ca2+ channel function. J. Cell Biol. 169, 435–445 (2005).
Brandman, O., Liou, J., Park, W. S. & Meyer, T. STIM2 is a feedback regulator that stabilizes basal cytosolic and endoplasmic reticulum Ca2+ levels. Cell 131, 1327–1339 (2007).
Feske, S. et al. A mutation in Orai1 causes immune deficiency by abrogating CRAC channel function. Nature 441, 179–185 (2006).
Vig, M. et al. CRACM1 is a plasma membrane protein essential for store-operated Ca2+ entry. Science 312, 1220–1223 (2006).
Zhang, S. L. et al. Genome-wide RNAi screen of Ca2+ influx identifies genes that regulate Ca2+ release-activated Ca2+ channel activity. Proc. Natl Acad. Sci. USA 103, 9357–9362 (2006).
Mercer, J. C. et al. Large store-operated calcium selective currents due to co-expression of Orai1 or Orai2 with the intracellular calcium sensor, Stim1. J. Biol. Chem. 281, 24979–24990 (2006).
Peinelt, C. et al. Amplification of CRAC current by STIM1 and CRACM1 (Orai1). Nat. Cell Biol. 8, 771–773 (2006).
Prakriya, M. et al. Orai1 is an essential pore subunit of the CRAC channel. Nature 443, 230–233 (2006).
Soboloff, J. et al. Orai1 and STIM reconstitute store-operated calcium channel function. J. Biol. Chem. 281, 20661–20665 (2006).
Vig, M. et al. CRACM1 multimers form the ion-selective pore of the CRAC channel. Curr. Biol. 16, 2073–2079 (2006).
Lioudyno, M. I. et al. Orai1 and STIM1 move to the immunological synapse and are up-regulated during T cell activation. Proc. Natl Acad. Sci. USA 105, 2011–2016 (2008).
Feske, S. et al. Severe combined immunodeficiency due to defective binding of the nuclear factor of activated T cells in T lymphocytes of two male siblings. Eur. J. Immunol. 26, 2119–2126 (1996).
Fuchs, S. et al. Antiviral and regulatory T cell immunity in a patient with stromal interaction molecule 1 deficiency. J. Immunol. 188, 1523–1533 (2012).
Le Deist, F. et al. A primary T cell immunodeficiency associated with defective transmembrane calcium influx. Blood 85, 1053–1062 (1995).
Picard, C. et al. STIM1 mutation associated with a syndrome of immunodeficiency and autoimmunity. N. Engl. J. Med. 360, 1971–1980 (2009).
Vaeth, M. et al. Store-operated Ca2+ entry controls clonal expansion of T cells through metabolic reprogramming. Immunity 47, 664–679 (2017). This is an outstanding paper providing evidence for the role of SOCE in T cell metabolism and immunity through control of glycolysis and oxidative phosphorylation genes.
Dolmetsch, R. E., Lewis, R. S., Goodnow, C. C. & Healy, J. I. Differential activation of transcription factors induced by Ca2+ response amplitude and duration. Nature 386, 855–858 (1997).
Partiseti, M. et al. The calcium current activated by T cell receptor and store depletion in human lymphocytes is absent in a primary immunodeficiency. J. Biol. Chem. 269, 32327–32335 (1994).
Lacruz, R. S. & Feske, S. Diseases caused by mutations in ORAI1 and STIM1. Ann. NY Acad. Sci. 1356, 45–79 (2015).
Vaeth, M. & Feske, S. Ion channelopathies of the immune system. Curr. Opin. Immunol. 52, 39–50 (2018).
Oh-Hora, M. et al. Agonist-selected T cell development requires strong T cell receptor signaling and store-operated calcium entry. Immunity 38, 881–895 (2013).
Vig, M. et al. Defective mast cell effector functions in mice lacking the CRACM1 pore subunit of store-operated calcium release-activated calcium channels. Nat. Immunol. 9, 89–96 (2008).
Oh-Hora, M. et al. Dual functions for the endoplasmic reticulum calcium sensors STIM1 and STIM2 in T cell activation and tolerance. Nat. Immunol. 9, 432–443 (2008).
Vaeth, M. et al. ORAI2 modulates store-operated calcium entry and T cell-mediated immunity. Nat. Commun. 8, 14714 (2017). This paper provides the first evidence that ORAI2 channels act as negative modulators of SOCE and T cell immunity.
Kaufmann, U. et al. Selective ORAI1 inhibition ameliorates autoimmune central nervous system inflammation by suppressing effector but not regulatory T cell function. J. Immunol. 196, 573–585 (2016).
Kim, K. D. et al. Calcium signaling via Orai1 is essential for induction of the nuclear orphan receptor pathway to drive Th17 differentiation. J. Immunol. 192, 110–122 (2014).
Wang, X. et al. Distinct Orai-coupling domains in STIM1 and STIM2 define the Orai-activating site. Nat. Commun. 5, 3183 (2014).
Vaeth, M. et al. Store-operated Ca2+ entry in follicular T cells controls humoral immune responses and autoimmunity. Immunity 44, 1350–1364 (2016).
Kim, K. D. et al. ORAI1 deficiency impairs activated T cell death and enhances T cell survival. J. Immunol. 187, 3620–3630 (2011).
Srikanth, S., Woo, J. S., Sun, Z. & Gwack, Y. Immunological disorders: regulation of Ca2+ signaling in T lymphocytes. Adv. Exp. Med. Biol. 993, 397–424 (2017).
Robbs, B. K., Cruz, A. L., Werneck, M. B., Mognol, G. P. & Viola, J. P. Dual roles for NFAT transcription factor genes as oncogenes and tumor suppressors. Mol. Cell. Biol. 28, 7168–7181 (2008).
Srinivasan, M. & Frauwirth, K. A. Reciprocal NFAT1 and NFAT2 nuclear localization in CD8+ anergic T cells is regulated by suboptimal calcium signaling. J. Immunol. 179, 3734–3741 (2007).
Desvignes, L. et al. STIM1 controls T cell-mediated immune regulation and inflammation in chronic infection. J. Clin. Invest. 125, 2347–2362 (2015).
Tsvilovskyy, V. et al. Deletion of Orai2 augments endogenous CRAC currents and degranulation in mast cells leading to enhanced anaphylaxis. Cell Calcium 71, 24–33 (2018).
Shuttleworth, T. J. Selective activation of distinct Orai channels by STIM1. Cell Calcium 63, 40–42 (2017).
Desai, P. N. et al. Multiple types of calcium channels arising from alternative translation initiation of the Orai1 message. Sci. Signal. 8, ra74 (2015).
Gonzalez-Cobos, J. C. et al. Store-independent Orai1/3 channels activated by intracrine leukotriene C4: role in neointimal hyperplasia. Circ. Res. 112, 1013–1025 (2013).
Zhang, X. et al. Mechanisms of STIM1 activation of store-independent leukotriene C4-regulated Ca2+ channels. Mol. Cell. Biol. 33, 3715–3723 (2013).
Zhang, X. et al. Complex role of STIM1 in the activation of store-independent Orai1/3 channels. J. Gen. Physiol. 143, 345–359 (2014).
Bogeski, I. et al. Differential redox regulation of ORAI ion channels: a mechanism to tune cellular calcium signaling. Sci. Signal. 3, ra24 (2010).
Liu, S., Kiyoi, T., Takemasa, E. & Maeyama, K. Systemic lentivirus-mediated delivery of short hairpin RNA targeting calcium release-activated calcium channel 3 as gene therapy for collagen-induced arthritis. J. Immunol. 194, 76–83 (2015).
Wenning, A. S. et al. TRP expression pattern and the functional importance of TRPC3 in primary human T cells. Biochim. Biophys. Acta 1813, 412–423 (2011).
Philipp, S. et al. TRPC3 mediates T cell receptor-dependent calcium entry in human T-lymphocytes. J. Biol. Chem. 278, 26629–26638 (2003).
Beck, A., Kolisek, M., Bagley, L. A., Fleig, A. & Penner, R. Nicotinic acid adenine dinucleotide phosphate and cyclic ADP-ribose regulate TRPM2 channels in T lymphocytes. FASEB J. 20, 962–964 (2006).
Guse, A. H. et al. Regulation of calcium signalling in T lymphocytes by the second messenger cyclic ADP-ribose. Nature 398, 70–73 (1999).
Melzer, N., Hicking, G., Gobel, K. & Wiendl, H. TRPM2 cation channels modulate T cell effector functions and contribute to autoimmune CNS inflammation. PLOS ONE 7, e47617 (2012).
Launay, P. et al. TRPM4 is a Ca2+-activated nonselective cation channel mediating cell membrane depolarization. Cell 109, 397–407 (2002).
Launay, P. et al. TRPM4 regulates calcium oscillations after T cell activation. Science 306, 1374–1377 (2004).
Weber, K. S., Hildner, K., Murphy, K. M. & Allen, P. M. Trpm4 differentially regulates Th1 and Th2 function by altering calcium signaling and NFAT localization. J. Immunol. 185, 2836–2846 (2010).
Zhang, X. et al. Unequal death in T helper cell (Th)1 and Th2 effectors: Th1, but not Th2, effectors undergo rapid Fas/FasL-mediated apoptosis. J. Exp. Med. 185, 1837–1849 (1997).
Chandy, K. G. et al. K+ channels as targets for specific immunomodulation. Trends Pharmacol. Sci. 25, 280–289 (2004).
Jin, J. et al. Deletion of Trpm7 disrupts embryonic development and thymopoiesis without altering Mg2+ homeostasis. Science 322, 756–760 (2008).
Faouzi, M., Kilch, T., Horgen, F. D., Fleig, A. & Penner, R. The TRPM7 channel kinase regulates store-operated calcium entry. J. Physiol. 595, 3165–3180 (2017).
Beesetty, P. et al. Inactivation of TRPM7 kinase in mice results in enlarged spleens, reduced T cell proliferation and diminished store-operated calcium entry. Sci. Rep. 8, 3023 (2018).
Romagnani, A. et al. TRPM7 kinase activity is essential for T cell colonization and alloreactivity in the gut. Nat. Commun. 8, 1917 (2017).
Desai, B. N. et al. Cleavage of TRPM7 releases the kinase domain from the ion channel and regulates its participation in Fas-induced apoptosis. Dev. Cell 22, 1149–1162 (2012).
Bertin, S. et al. The ion channel TRPV1 regulates the activation and proinflammatory properties of CD4+ T cells. Nat. Immunol. 15, 1055–1063 (2014).
Samivel, R. et al. The role of TRPV1 in the CD4+ T cell-mediated inflammatory response of allergic rhinitis. Oncotarget 7, 148–160 (2016).
Bertin, S. et al. The TRPA1 ion channel is expressed in CD4+ T cells and restrains T cell-mediated colitis through inhibition of TRPV1. Gut 66, 1584–1596 (2017).
Di Virgilio, F., Sarti, A. C. & Grassi, F. Modulation of innate and adaptive immunity by P2X ion channels. Curr. Opin. Immunol. 52, 51–59 (2018).
Di Virgilio, F., Dal Ben, D., Sarti, A. C., Giuliani, A. L. & Falzoni, S. The P2X7 receptor in infection and inflammation. Immunity 47, 15–31 (2017). This paper provides an excellent overview on the role of P2XR7 in regulating innate and adaptive immunity.
Coutinho-Silva, R., Knight, G. E. & Burnstock, G. Impairment of the splenic immune system in P2X2/P2X3 knockout mice. Immunobiology 209, 661–668 (2005).
Cockayne, D. A. et al. P2X2 knockout mice and P2X2/P2X3 double knockout mice reveal a role for the P2X2 receptor subunit in mediating multiple sensory effects of ATP. J. Physiol. 567, 621–639 (2005).
Abramowski, P., Ogrodowczyk, C., Martin, R. & Pongs, O. A truncation variant of the cation channel P2RX5 is upregulated during T cell activation. PLOS ONE 9, e104692 (2014).
Woehrle, T. et al. Pannexin-1 hemichannel-mediated ATP release together with P2X1 and P2X4 receptors regulate T cell activation at the immune synapse. Blood 116, 3475–3484 (2010).
Ledderose, C. et al. Mitochondrial dysfunction, depleted purinergic signaling, and defective T cell vigilance and immune defense. J. Infect. Dis. 213, 456–464 (2016).
Wang, C. M., Ploia, C., Anselmi, F., Sarukhan, A. & Viola, A. Adenosine triphosphate acts as a paracrine signaling molecule to reduce the motility of T cells. EMBO J. 33, 1354–1364 (2014).
Manohar, M. et al. ATP release and autocrine signaling through P2X4 receptors regulate gammadelta T cell activation. J. Leukoc. Biol. 92, 787–794 (2012).
Frascoli, M., Marcandalli, J., Schenk, U. & Grassi, F. Purinergic P2X7 receptor drives T cell lineage choice and shapes peripheral gammadelta cells. J. Immunol. 189, 174–180 (2012).
Schenk, U. et al. ATP inhibits the generation and function of regulatory T cells through the activation of purinergic P2X receptors. Sci. Signal 4, ra12 (2011).
Vergani, A. et al. Effect of the purinergic inhibitor oxidized ATP in a model of islet allograft rejection. Diabetes 62, 1665–1675 (2013).
Vergani, A. et al. Long-term heart transplant survival by targeting the ionotropic purinergic receptor P2X7. Circulation 127, 463–475 (2013).
Koo, T. Y. et al. The P2X7 receptor antagonist, oxidized adenosine triphosphate, ameliorates renal ischemia-reperfusion injury by expansion of regulatory T cells. Kidney Int. 92, 415–431 (2017).
Sharp, A. J. et al. P2X7 deficiency suppresses development of experimental autoimmune encephalomyelitis. J. Neuroinflamm. 5, 33 (2008).
Takeda, A. et al. Crucial role of P2X7 receptor for effector T cell activation in experimental autoimmune uveitis. Jpn J. Ophthalmol. 62, 398–406 (2018).
Salles, E. M. et al. P2X7 receptor drives Th1 cell differentiation and controls the follicular helper T cell population to protect against Plasmodium chabaudi malaria. PLOS Pathog. 13, e1006595 (2017).
Hofman, P. et al. Genetic and pharmacological inactivation of the purinergic P2RX7 receptor dampens inflammation but increases tumor incidence in a mouse model of colitis-associated cancer. Cancer Res. 75, 835–845 (2015).
Borges da Silva, H. et al. The purinergic receptor P2RX7 directs metabolic fitness of long-lived memory CD8+ T cells. Nature 559, 264–268 (2018).
Chen, L. & Brosnan, C. F. Exacerbation of experimental autoimmune encephalomyelitis in P2X7R−/− mice: evidence for loss of apoptotic activity in lymphocytes. J. Immunol. 176, 3115–3126 (2006).
Taylor, S. R. et al. Lymphocytes from P2X7-deficient mice exhibit enhanced P2X7 responses. J. Leukoc. Biol. 85, 978–986 (2009).
Shinohara, Y. & Tsukimoto, M. Guanine and inosine nucleotides/nucleosides suppress murine T cell activation. Biochem. Biophys. Res. Commun. 498, 764–768 (2018).
Lecciso, M. et al. ATP release from chemotherapy-treated dying leukemia cells elicits an immune suppressive effect by increasing regulatory T cells and tolerogenic dendritic cells. Front. Immunol. 8, 1918 (2017).
Badou, A., Jha, M. K., Matza, D. & Flavell, R. A. Emerging roles of L-type voltage-gated and other calcium channels in T lymphocytes. Front. Immunol. 4, 243 (2013).
Robert, V., Triffaux, E., Savignac, M. & Pelletier, L. Singularities of calcium signaling in effector T-lymphocytes. Biochim. Biophys. Acta 1833, 1595–1602 (2013).
Navedo, M. F. & Santana, L. F. CaV1.2 sparklets in heart and vascular smooth muscle. J. Mol. Cell Cardiol. 58, 67–76 (2013).
Navedo, M. F., Amberg, G. C., Nieves, M., Molkentin, J. D. & Santana, L. F. Mechanisms underlying heterogeneous Ca2+ sparklet activity in arterial smooth muscle. J. Gen. Physiol. 127, 611–622 (2006).
Nieves-Cintron, M., Amberg, G. C., Navedo, M. F., Molkentin, J. D. & Santana, L. F. The control of Ca2+ influx and NFATc3 signaling in arterial smooth muscle during hypertension. Proc. Natl Acad. Sci. USA 105, 15623–15628 (2008).
Dixon, R. E. et al. Graded Ca2+/calmodulin-dependent coupling of voltage-gated CaV1.2 channels. eLife 4, e05608 (2015).
Dixon, R. E., Yuan, C., Cheng, E. P., Navedo, M. F. & Santana, L. F. Ca2+ signaling amplification by oligomerization of L-type Cav1.2 channels. Proc. Natl Acad. Sci. USA 109, 1749–1754 (2012).
Navedo, M. F., Amberg, G. C., Votaw, V. S. & Santana, L. F. Constitutively active L-type Ca2+ channels. Proc. Natl Acad. Sci. USA 102, 11112–11117 (2005).
Bannister, R. A. & Beam, K. G. CaV1.1: the atypical prototypical voltage-gated Ca2+ channel. Biochim. Biophys. Acta 1828, 1587–1597 (2013).
Matza, D. et al. T cell receptor mediated calcium entry requires alternatively spliced Cav1.1 channels. PLOS ONE 11, e0147379 (2016).
Jha, M. K. et al. Defective survival of naive CD8+ T lymphocytes in the absence of the β3 regulatory subunit of voltage-gated calcium channels. Nat. Immunol. 10, 1275–1282 (2009).
Jha, A. et al. Essential roles for Cavβ2 and Cav1 channels in thymocyte development and T cell homeostasis. Sci. Signal 8, ra103 (2015).
Chandrasekhar, R., Alzayady, K. J., Wagner, L. E. 2nd & Yule, D. I. Unique regulatory properties of heterotetrameric inositol 1,4,5-trisphosphate receptors revealed by studying concatenated receptor constructs. J. Biol. Chem. 291, 4846–4860 (2016).
Jayaraman, T., Ondriasova, E., Ondrias, K., Harnick, D. J. & Marks, A. R. The inositol 1,4,5-trisphosphate receptor is essential for T cell receptor signaling. Proc. Natl Acad. Sci. USA 92, 6007–6011 (1995).
Jayaraman, T. & Marks, A. R. Calcineurin is downstream of the inositol 1,4,5-trisphosphate receptor in the apoptotic and cell growth pathways. J. Biol. Chem. 275, 6417–6420 (2000).
Ouyang, K. et al. Loss of IP3R-dependent Ca2+ signalling in thymocytes leads to aberrant development and acute lymphoblastic leukemia. Nat. Commun. 5, 4814 (2014).
Wolf, I. M. A. & Guse, A. H. Ca2+ microdomains in T-lymphocytes. Front. Oncol. 7, 73 (2017).
Wolf, I. M. et al. Frontrunners of T cell activation: initial, localized Ca2+ signals mediated by NAADP and the type 1 ryanodine receptor. Sci. Signal 8, ra102 (2015).
Kunerth, S. et al. Amplification and propagation of pacemaker Ca2+ signals by cyclic ADP-ribose and the type 3 ryanodine receptor in T cells. J. Cell Sci. 117, 2141–2149 (2004).
Dammermann, W. et al. NAADP-mediated Ca2+ signaling via type 1 ryanodine receptor in T cells revealed by a synthetic NAADP antagonist. Proc. Natl Acad. Sci. USA 106, 10678–10683 (2009).
Dadsetan, S., Zakharova, L., Molinski, T. F. & Fomina, A. F. Store-operated Ca2+ influx causes Ca2+ release from the intracellular Ca2+ channels that is required for T cell activation. J. Biol. Chem. 283, 12512–12519 (2008).
Thakur, P., Dadsetan, S. & Fomina, A. F. Bidirectional coupling between ryanodine receptors and Ca2+ release-activated Ca2+ (CRAC) channel machinery sustains store-operated Ca2+ entry in human T lymphocytes. J. Biol. Chem. 287, 37233–37244 (2012).
Takeshima, H. et al. Generation and characterization of mutant mice lacking ryanodine receptor type 3. J. Biol. Chem. 271, 19649–19652 (1996).
Davis, L. C., Platt, F. M. & Galione, A. Preferential coupling of the NAADP pathway to exocytosis in T-cells. Messenger (Los Angel) 4, 53–66 (2015).
Steen, M., Kirchberger, T. & Guse, A. H. NAADP mobilizes calcium from the endoplasmic reticular Ca2+ store in T-lymphocytes. J. Biol. Chem. 282, 18864–18871 (2007).
Gerasimenko, J. V., Sherwood, M., Tepikin, A. V., Petersen, O. H. & Gerasimenko, O. V. NAADP, cADPR and IP3 all release Ca2+ from the endoplasmic reticulum and an acidic store in the secretory granule area. J. Cell Sci. 119, 226–238 (2006).
Mehta, M. M., Weinberg, S. E. & Chandel, N. S. Mitochondrial control of immunity: beyond ATP. Nat. Rev. Immunol. 17, 608–620 (2017).
Bagur, R. & Hajnoczky, G. Intracellular Ca2+ sensing: its role in calcium homeostasis and signaling. Mol. Cell 66, 780–788 (2017).
Csordas, G., Weaver, D. & Hajnoczky, G. Endoplasmic reticular-mitochondrial contactology: structure and signaling functions. Trends Cell Biol. 28, 523–540 (2018). This is an excellent review on the intimate crosstalk between ER and mitochondrial Ca 2+ signalling networks, their structure, organization and protein composition and novel methods to study them.
Santo-Domingo, J. & Demaurex, N. Calcium uptake mechanisms of mitochondria. Biochim. Biophys. Acta 1797, 907–912 (2010).
Pathak, T. & Trebak, M. Mitochondrial Ca2+ signaling. Pharmacol. Ther. 192, 112–123 (2018).
Quintana, A. & Hoth, M. Mitochondrial dynamics and their impact on T cell function. Cell Calcium 52, 57–63 (2012).
Junker, C. & Hoth, M. Immune synapses: mitochondrial morphology matters. EMBO J. 30, 1187–1189 (2011).
Hoth, M., Fanger, C. M. & Lewis, R. S. Mitochondrial regulation of store-operated calcium signaling in T lymphocytes. J. Cell Biol. 137, 633–648 (1997).
Hoth, M., Button, D. C. & Lewis, R. S. Mitochondrial control of calcium-channel gating: a mechanism for sustained signaling and transcriptional activation in T lymphocytes. Proc. Natl Acad. Sci. USA 97, 10607–10612 (2000).
Quintana, A. et al. T cell activation requires mitochondrial translocation to the immunological synapse. Proc. Natl Acad. Sci. USA 104, 14418–14423 (2007).
Quintana, A. et al. Calcium microdomains at the immunological synapse: how ORAI channels, mitochondria and calcium pumps generate local calcium signals for efficient T cell activation. EMBO J. 30, 3895–3912 (2011).
Ritchie, M. F., Samakai, E. & Soboloff, J. STIM1 is required for attenuation of PMCA-mediated Ca2+ clearance during T cell activation. EMBO J. 31, 1123–1133 (2012).
Verkhratsky, A., Trebak, M., Perocchi, F., Khananshvili, D. & Sekler, I. Crosslink between calcium and sodium signalling. Exp. Physiol. 103, 157–169 (2018).
Jiang, D., Zhao, L. & Clapham, D. E. Genome-wide RNAi screen identifies Letm1 as a mitochondrial Ca2+/H+ antiporter. Science 326, 144–147 (2009).
Kim, B., Takeuchi, A., Koga, O., Hikida, M. & Matsuoka, S. Pivotal role of mitochondrial Na+- Ca2+ exchange in antigen receptor mediated Ca2+ signalling in DT40 and A20 B lymphocytes. J. Physiol. 590, 459–474 (2012).
Finetti, F., Onnis, A. & Baldari, C. T. Regulation of vesicular traffic at the T cell immune synapse: lessons from the primary cilium. Traffic 16, 241–249 (2015).
Voskoboinik, I., Whisstock, J. C. & Trapani, J. A. Perforin and granzymes: function, dysfunction and human pathology. Nat. Rev. Immunol. 15, 388–400 (2015).
Benzing, C., Rossy, J. & Gaus, K. Do signalling endosomes play a role in T cell activation? FEBS J. 280, 5164–5176 (2013).
Brailoiu, E. et al. Essential requirement for two-pore channel 1 in NAADP-mediated calcium signaling. J. Cell Biol. 186, 201–209 (2009).
Calcraft, P. J. et al. NAADP mobilizes calcium from acidic organelles through two-pore channels. Nature 459, 596–600 (2009).
Zong, X. et al. The two-pore channel TPCN2 mediates NAADP-dependent Ca2+-release from lysosomal stores. Pflugers Arch. 458, 891–899 (2009).
Galione, A. A primer of NAADP-mediated Ca2+ signalling: From sea urchin eggs to mammalian cells. Cell Calcium 58, 27–47 (2015).
Wang, X. et al. TPC proteins are phosphoinositide- activated sodium-selective ion channels in endosomes and lysosomes. Cell 151, 372–383 (2012).
Cang, C. et al. mTOR regulates lysosomal ATP-sensitive two-pore Na+ channels to adapt to metabolic state. Cell 152, 778–790 (2013).
Li, X. et al. Genetically encoded fluorescent probe to visualize intracellular phosphatidylinositol 3,5-bisphosphate localization and dynamics. Proc. Natl Acad. Sci. USA 110, 21165–21170 (2013).
Davis, L. C. et al. NAADP activates two-pore channels on T cell cytolytic granules to stimulate exocytosis and killing. Curr. Biol. 22, 2331–2337 (2012).
Cuajungco, M. P., Silva, J., Habibi, A. & Valadez, J. A. The mucolipin-2 (TRPML2) ion channel: a tissue-specific protein crucial to normal cell function. Pflugers Arch. 468, 177–192 (2016).
Cheng, X., Shen, D., Samie, M. & Xu, H. Mucolipins: intracellular TRPML1-3 channels. FEBS Lett. 584, 2013–2021 (2010).
Sun, L., Hua, Y., Vergarajauregui, S., Diab, H. I. & Puertollano, R. Novel role of TRPML2 in the regulation of the innate immune response. J. Immunol. 195, 4922–4932 (2015).
Venkatachalam, K., Hofmann, T. & Montell, C. Lysosomal localization of TRPML3 depends on TRPML2 and the mucolipidosis-associated protein TRPML1. J. Biol. Chem. 281, 17517–17527 (2006).
Dong, X. P. et al. PI(3,5)P2 controls membrane trafficking by direct activation of mucolipin Ca2+ release channels in the endolysosome. Nat. Commun. 1, 38 (2010).
Samie, M. et al. A TRP channel in the lysosome regulates large particle phagocytosis via focal exocytosis. Dev. Cell 26, 511–524 (2013).
LaPlante, J. M. et al. Lysosomal exocytosis is impaired in mucolipidosis type IV. Mol. Genet. Metab. 89, 339–348 (2006).
Zhang, X., Li, X. & Xu, H. Phosphoinositide isoforms determine compartment-specific ion channel activity. Proc. Natl Acad. Sci. USA 109, 11384–11389 (2012).
Feng, X. et al. Drosophila TRPML forms PI(3,5)P2-activated cation channels in both endolysosomes and plasma membrane. J. Biol. Chem. 289, 4262–4272 (2014).
Zhong, X. Z. et al. Inhibition of transient receptor potential channel mucolipin-1 (TRPML1) by lysosomal adenosine involved in severe combined immunodeficiency diseases. J. Biol. Chem. 292, 3445–3455 (2017).
Whitmore, K. V. & Gaspar, H. B. Adenosine deaminase deficiency - more than just an immunodeficiency. Front. Immunol. 7, 314 (2016).
Shuai, J. & Parker, I. Optical single-channel recording by imaging Ca2+ flux through individual ion channels: theoretical considerations and limits to resolution. Cell Calcium 37, 283–299 (2005).
Potier, M. & Trebak, M. New developments in the signaling mechanisms of the store-operated calcium entry pathway. Pflugers Arch. 457, 405–415 (2008).
Gwack, Y., Feske, S., Srikanth, S., Hogan, P. G. & Rao, A. Signalling to transcription: store-operated Ca2+ entry and NFAT activation in lymphocytes. Cell Calcium 42, 145–156 (2007).
Fukushima, M., Tomita, T., Janoshazi, A. & Putney, J. W. Alternative translation initiation gives rise to two isoforms of Orai1 with distinct plasma membrane mobilities. J. Cell Sci. 125, 4354–4361 (2012).
Ruhle, B. & Trebak, M. Emerging roles for native Orai Ca2+ channels in cardiovascular disease. Curr. Top. Membr. 71, 209–235 (2013).
Willoughby, D. et al. Direct binding between Orai1 and AC8 mediates dynamic interplay between Ca2+ and cAMP signaling. Sci. Signal. 5, ra29 (2012). This is an article identifying the physical interaction between ORAI1 and adenylyl cyclase 8 as a determinant for Ca 2+ and cAMP signalling crosstalk.
Zhang, W. et al. Leukotriene-C4 synthase, a critical enzyme in the activation of store-independent Orai1/Orai3 channels, is required for neointimal hyperplasia. J. Biol. Chem. 290, 5015–5027 (2015).
Krishnamoorthy, M. et al. The channel-kinase TRPM7 regulates antigen gathering and internalization in B cells. Sci. Signal. 11, eaah6692 (2018).
Mammucari, C. et al. Mitochondrial calcium uptake in organ physiology: from molecular mechanism to animal models. Pflugers Arch. 470, 1165–1179 (2018).
Ghosh, D. et al. Calcium channels in vascular smooth muscle. Adv. Pharmacol. 78, 49–87 (2017).
Guse, A. H. & Diercks, B. P. Integration of nicotinic acid adenine dinucleotide phosphate (NAADP)-dependent calcium signalling. J. Physiol. 596, 2735–2743 (2018).
Huang, P. et al. P2X4 forms functional ATP-activated cation channels on lysosomal membranes regulated by luminal pH. J. Biol. Chem. 289, 17658–17667 (2014).
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.
About this article
Cell Calcium (2020)
Novel findings of 18β‐glycyrrhetinic acid on sRAGE secretion through inhibition of transient receptor potential canonical channels in high‐glucose environment
Chemistry – An Asian Journal (2019)
Clinical & Translational Immunology (2019)