Calcium signals in lymphocytes contribute to the regulation of many cell functions, including lymphocyte differentiation into T helper 1 (TH1) and TH2 cells, T-cell and B-cell activation and anergy, gene transcription, and effector functions such as cytotoxic T lymphocyte (CTL)-mediated cytotoxicity.
Increases in intracellular Ca2+ levels result from engagement of immunoreceptors, including the T-cell receptor, the B-cell receptor and Fc receptors, as well as chemokine and co-stimulatory receptors.
The main pathway for increasing intracellular Ca2+ levels in lymphocytes is through store-operated calcium entry (SOCE) and the calcium-release-activated calcium (CRAC) channel.
The CRAC channel is highly selective for Ca2+ and has been carefully defined by its biophysical properties. ORAI1 (also known as CRACM1) has recently been identified as a subunit of the CRAC channel pore. ORAI1 is a tetraspanning plasma membrane protein, which is structurally unrelated to other known ion channels but it has two close homologues, ORAI2 and ORAI3.
Stromal interaction molecule 1 (STIM1) has recently been identified as an essential regulator of SOCE and CRAC channel function. STIM1 oligomerizes upon Ca2+ store depletion and distributes into a punctate pattern in parts of the ER that are apposed to the plasma membrane, where it presumably interacts, directly or indirectly, with ORAI1-containing CRAC channels.
Mutations in ORAI1 that result in a lack of functional CRAC channels and SOCE are characterized by a profound defect in T-cell activation and severe combined immunodeficiency (SCID) in humans.
Apart from SCID, abnormal lymphocyte Ca2+ signalling is associated with several human primary immunodeficiencies and is likely to contribute to the pathophysiology of autoimmune and inflammatory diseases. The SOCE/CRAC pathway is a potential target for therapeutical immune modulation.
Calcium signals in cells of the immune system participate in the regulation of cell differentiation, gene transcription and effector functions. An increase in intracellular levels of calcium ions (Ca2+) results from the engagement of immunoreceptors, such as the T-cell receptor, B-cell receptor and Fc receptors, as well as chemokine and co-stimulatory receptors. The major pathway that induces an increase in intracellular Ca2+ levels in lymphocytes is through store-operated calcium entry (SOCE) and calcium-release-activated calcium (CRAC) channels. This Review focuses on the role of Ca2+ signals in lymphocyte functions, the signalling pathways leading to Ca2+ influx, the function of the recently discovered regulators of Ca2+ influx (STIM and ORAI), and the relationship between Ca2+ signals and diseases of the immune system.
Subscribe to Journal
Get full journal access for 1 year
only $4.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Lewis, R. S. Calcium signaling mechanisms in T lymphocytes. Annu. Rev. Immunol. 19, 497–521 (2001).
Parekh, A. B. & Putney, J. W. Jr. Store-operated calcium channels. Physiol. Rev. 85, 757–810 (2005).
Prakriya, M. & Lewis, R. S. CRAC channels: activation, permeation, and the search for a molecular identity. Cell Calcium 33, 311–321 (2003). References 1–3 are detailed reviews of the biophysical properties, molecular nature and role of the CRAC and other store-operated Ca2+ channels.
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).
Le Deist, F. et al. A primary T-cell immunodeficiency associated with defective transmembrane calcium influx. Blood 85, 1053–1062 (1995).
Feske, S., Prakriya, M., Rao, A. & Lewis, R. S. A severe defect in CRAC Ca2+ channel activation and altered K+ channel gating in T cells from immunodeficient patients. J. Exp. Med. 202, 651–662 (2005).
Lewis, R. S. The molecular choreography of a store-operated calcium channel. Nature 446, 284–287 (2007). This review describes the discovery of STIM1 and ORAI1 as components of the SOCE pathway.
Asherson, G. L., Davey, M. J. & Goodford, P. J. Increased uptake of calcium by human lymphocytes treated with phytohaemagglutinin. J. Physiol. 206, 32P–33P (1970).
Whitfield, J. F., Perris, A. D. & Youdale, T. The role of calcium in the mitotic stimulation of rat thymocytes by detergents, agmatine and poly-L-lysine. Exp. Cell. Res. 53, 155–165 (1968).
Weiss, A., Imboden, J., Shoback, D. & Stobo, J. Role of T3 surface molecules in human T-cell activation: T3-dependent activation results in an increase in cytoplasmic free calcium. Proc. Natl Acad. Sci. USA 81, 4169–4173 (1984).
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).
Feske, S., Giltnane, J., Dolmetsch, R., Staudt, L. & Rao, A. Gene regulation by calcium influx in T lymphocytes. Nature Immunol. 2, 316–324 (2001). This study investigates the role of SOCE on global gene-expression patterns in T cells.
Feske, S. et al. A mutation in Orai1 causes immune deficiency by abrogating CRAC channel function. Nature 441, 179–185 (2006). This paper, together with references 78 and 79 , describes the initial identification of ORAI1 as a plasma membrane protein essential for SOCE. Mutations in ORAI1 are shown to be the cause of abrogated CRAC channel function in T cells from human patients with immunodeficiencies.
Feske, S., Okamura, H., Hogan, P. G. & Rao, A. Ca2+/calcineurin signalling in cells of the immune system. Biochem. Biophys. Res. Commun. 311, 1117–1132 (2003).
Hogan, P. G., Chen, L., Nardone, J. & Rao, A. Transcriptional regulation by calcium, calcineurin, and NFAT. Genes Dev. 17, 2205–2232 (2003).
Randriamampita, C. & Trautmann, A. Ca2+ signals and T lymphocytes; 'New mechanisms and functions in Ca2+ signalling'. Biol. Cell. 96, 69–78 (2004).
Gallo, E. M., Cante-Barrett, K. & Crabtree, G. R. Lymphocyte calcium signaling from membrane to nucleus. Nature Immunol. 7, 25–32 (2006).
Delon, J., Bercovici, N., Liblau, R. & Trautmann, A. Imaging antigen recognition by naive CD4+ T cells: compulsory cytoskeletal alterations for the triggering of an intracellular calcium response. Eur. J. Immunol. 28, 716–729 (1998).
Negulescu, P. A., Krasieva, T. B., Khan, A., Kerschbaum, H. H. & Cahalan, M. D. Polarity of T cell shape, motility, and sensitivity to antigen. Immunity 4, 421–430 (1996).
Bhakta, N. R., Oh, D. Y. & Lewis, R. S. Calcium oscillations regulate thymocyte motility during positive selection in the three-dimensional thymic environment. Nature Immunol. 6, 143–151 (2005). References 18 – 20 are imaging studies showing the relationship between intracellular Ca2+ concentrations and T-cell function, in particular T-cell motility, immunological synapse formation and positive selection of thymocytes.
Trambas, C. M. & Griffiths, G. M. Delivering the kiss of death. Nature Immunol. 4, 399–403 (2003).
Lyubchenko, T. A., Wurth, G. A. & Zweifach, A. Role of calcium influx in cytotoxic T lymphocyte lytic granule exocytosis during target cell killing. Immunity 15, 847–859 (2001). An elegant demonstration of the role of Ca2+ signals for the cytolytic function of CTLs.
Poenie, M., Tsien, R. Y. & Schmitt-Verhulst, A. M. Sequential activation and lethal hit measured by [Ca2+]i in individual cytolytic T cells and targets. EMBO J. 6, 2223–2232 (1987).
Macian, F. NFAT proteins: key regulators of T-cell development and function. Nature Rev. Immunol. 5, 472–484 (2005).
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). This paper elegantly shows how the shape and duration of Ca2+ influx influences the activation of different transcription factors and some of their target genes.
Cristillo, A. D. & Bierer, B. E. Identification of novel targets of immunosuppressive agents by cDNA-based microarray analysis. J. Biol. Chem. 277, 4465–4476 (2002).
Diehn, M. et al. Genomic expression programs and the integration of the CD28 costimulatory signal in T cell activation. Proc. Natl Acad. Sci. USA 99, 11796–11801 (2002).
Fanger, C. M., Hoth, M., Crabtree, G. R. & Lewis, R. S. Characterization of T cell mutants with defects in capacitative calcium entry: genetic evidence for the physiological roles of CRAC channels. J. Cell. Biol. 131, 655–667 (1995).
Macian, F. et al. Transcriptional mechanisms underlying lymphocyte tolerance. Cell 109, 719–731 (2002).
Winslow, M. M., Neilson, J. R. & Crabtree, G. R. Calcium signalling in lymphocytes. Curr. Opin. Immunol. 15, 299–307 (2003).
Gauld, S. B., Benschop, R. J., Merrell, K. T. & Cambier, J. C. Maintenance of B cell anergy requires constant antigen receptor occupancy and signaling. Nature Immunol. 6, 1160–1167 (2005).
Heissmeyer, V. & Rao, A. E3 ligases in T cell anergy—turning immune responses into tolerance. Sci. STKE 2004, pe29 (2004).
Heissmeyer, V. et al. Calcineurin imposes T cell unresponsiveness through targeted proteolysis of signaling proteins. Nature Immunol. 5, 255–265 (2004).
Rogers, P. R., Huston, G. & Swain, S. L. High antigen density and IL-2 are required for generation of CD4 effectors secreting Th1 rather than Th0 cytokines. J. Immunol. 161, 3844–3852 (1998).
Constant, S., Pfeiffer, C., Woodard, A., Pasqualini, T. & Bottomly, K. Extent of T cell receptor ligation can determine the functional differentiation of naive CD4+ T cells. J. Exp. Med. 182, 1591–1596 (1995).
Leitenberg, D. & Bottomly, K. Regulation of naive T cell differentiation by varying the potency of TCR signal transduction. Semin. Immunol. 11, 283–292 (1999).
Sloan-Lancaster, J., Steinberg, T. H. & Allen, P. M. Selective loss of the calcium ion signaling pathway in T cells maturing toward a T helper 2 phenotype. J. Immunol. 159, 1160–1168 (1997).
Gajewski, T. F., Schell, S. R. & Fitch, F. W. Evidence implicating utilization of different T cell receptor-associated signaling pathways by TH1 and TH2 clones. J. Immunol. 144, 4110–4120 (1990).
von Boehmer, H. & Fehling, H. J. Structure and function of the pre-T cell receptor. Annu. Rev. Immunol. 15, 433–452 (1997).
Clements, J. L. et al. Requirement for the leukocyte-specific adapter protein SLP-76 for normal T cell development. Science 281, 416–419 (1998).
Pivniouk, V. et al. Impaired viability and profound block in thymocyte development in mice lacking the adaptor protein SLP-76. Cell 94, 229–238 (1998).
Zhang, W. et al. Essential role of LAT in T cell development. Immunity 10, 323–332 (1999).
Liao, X. C. & Littman, D. R. Altered T cell receptor signaling and disrupted T cell development in mice lacking Itk. Immunity 3, 757–769 (1995).
Kurosaki, T. et al. Regulation of the phospholipase C-γ2 pathway in B cells. Immunol. Rev. 176, 19–29 (2000).
Lucas, J. A., Miller, A. T., Atherly, L. O. & Berg, L. J. The role of Tec family kinases in T cell development and function. Immunol. Rev. 191, 119–138 (2003).
van Leeuwen, J. E. & Samelson, L. E. T cell antigen-receptor signal transduction. Curr. Opin. Immunol. 11, 242–248 (1999).
Hoth, M. & Penner, R. Depletion of intracellular calcium stores activates a calcium current in mast cells. Nature 355, 353–356 (1992).
Zweifach, A. & Lewis, R. S. Mitogen-regulated Ca2+ current of T lymphocytes is activated by depletion of intracellular Ca2+ stores. Proc. Natl Acad. Sci. USA 90, 6295–6299 (1993).
Prakriya, M. & Lewis, R. S. Potentiation and inhibition of Ca2+ release-activated Ca2+ channels by 2-aminoethyldiphenyl borate (2-APB) occurs independently of IP3 receptors. J. Physiol. 536, 3–19 (2001).
Hsu, S. et al. Fundamental Ca2+ signaling mechanisms in mouse dendritic cells: CRAC is the major Ca2+ entry pathway. J. Immunol. 166, 6126–6133 (2001).
Yue, L., Peng, J. B., Hediger, M. A. & Clapham, D. E. CaT1 manifests the pore properties of the calcium-release-activated calcium channel. Nature 410, 705–709 (2001).
Mori, Y. et al. Transient receptor potential 1 regulates capacitative Ca2+ entry and Ca2+ release from endoplasmic reticulum in B lymphocytes. J. Exp. Med. 195, 673–681 (2002).
Clapham, D. E. Sorting out MIC, TRP, and CRAC ion channels. J. Gen. Physiol. 120, 217–220 (2002).
Voets, T. et al. CaT1 and the calcium release-activated calcium channel manifest distinct pore properties. J. Bio. Chem. 276, 47767–47770 (2001).
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).
Solle, M. et al. Altered cytokine production in mice lacking P2X7 receptors. J. Biol. Chem. 276, 125–132 (2001).
Labasi, J. M. et al. Absence of the P2X7 receptor alters leukocyte function and attenuates an inflammatory response. J. Immunol. 168, 6436–6445 (2002).
Adriouch, S. et al. Cutting edge: a natural P451L mutation in the cytoplasmic domain impairs the function of the mouse P2X7 receptor. J. Immunol. 169, 4108–4112 (2002).
Putney, J. W. Jr. A model for receptor-regulated calcium entry. Cell Calcium 7, 1–12 (1986).
Randriamampita, C. & Tsien, R. Y. Emptying of intracellular Ca2+ stores releases a novel small messenger that stimulates Ca2+ influx. Nature 364, 809–814 (1993).
Patterson, R. L., van Rossum, D. B. & Gill, D. L. Store-operated Ca2+ entry: evidence for a secretion-like coupling model. Cell 98, 487–499 (1999).
Yao, Y., Ferrer-Montiel, A. V., Montal, M. & Tsien, R. Y. Activation of store-operated Ca2+ current in Xenopus oocytes requires SNAP-25 but not a diffusible messenger. Cell 98, 475–485 (1999).
Roos, J. et al. STIM1, an essential and conserved component of store-operated Ca2+ channel function. J. Cell Biol. 169, 435–445 (2005).
Liou, J. et al. STIM is a Ca2+ sensor essential for Ca2+-store-depletion-triggered Ca2+ influx. Curr. Biol. 15, 1235–1241 (2005). References 63 and 64 report the identification of STIM1 as an essential regulator of SOCE through RNAi screens and demonstrate a role for the EF-hand domain of STIM1 in sensing Ca2+ levels in the ER and show aggregation of STIM1 in puncta in the ER membrane following Ca2+ store depletion.
Oritani, K. & Kincade, P. W. Identification of stromal cell products that interact with pre-B cells. J. Cell Biol. 134, 771–782 (1996).
Sabbioni, S., Barbanti-Brodano, G., Croce, C. M. & Negrini, M. GOK: a gene at 11p15 involved in rhabdomyosarcoma and rhabdoid tumor development. Cancer Res. 57, 4493–4497 (1997).
Manji, S. S. et al. STIM1: a novel phosphoprotein located at the cell surface. Biochim. Biophys. Acta 1481, 147–155 (2000).
Zhang, S. L. et al. STIM1 is a Ca2+ sensor that activates CRAC channels and migrates from the Ca2+ store to the plasma membrane. Nature 437, 902–905 (2005).
Spassova, M. A. et al. STIM1 has a plasma membrane role in the activation of store-operated Ca2+ channels. Proc. Natl Acad. Sci. USA 103, 4040–4045 (2006).
Baba, Y. et al. Coupling of STIM1 to store-operated Ca2+ entry through its constitutive and inducible movement in the endoplasmic reticulum. Proc. Natl Acad. Sci. USA 103, 16704–16709 (2006).
Liou, J., Fivaz, M., Inoue, T. & Meyer, T. Live-cell imaging reveals sequential oligomerization and local plasma membrane targeting of stromal interaction molecule 1 after Ca2+ store depletion. Proc. Natl Acad. Sci. USA 104, 9301–9306 (2007).
Luik, R., Wu, M., Buchanan, J. & Lewis, R. S. The elementary unit of store-operated Ca2+ entry: local activation of CRAC channels by STIM1 at ER-plasma membrane junctions. J. Cell Biol. 174, 815–825 (2006). References 72 and 75 are elegant imaging studies showing the presence of STIM1 clusters in regions of the ER apposed to the plasma membrane and the co-localization of STIM1 with sites of Ca2+ influx.
Hauser, C. T. & Tsien, R. Y. A hexahistidine-Zn2+-dye label reveals STIM1 surface exposure. Proc. Natl Acad. Sci. USA 104, 3693–3697 (2007).
Williams, R. T. et al. Stromal interaction molecule 1 (STIM1), a transmembrane protein with growth suppressor activity, contains an extracellular SAM domain modified by N-linked glycosylation. Biochim. Biophys. Acta 1596, 131–137 (2002).
Wu, M., Buchanan, J., Luik, R. & Lewis, R. S. Ca2+ store depeltion causes STIM1 to accumulate in ER regions closely associated with the plasma membrane. J. Cell Biol. 174, 803–813 (2006).
Williams, R. T. et al. Identification and characterization of the STIM (stromal interaction molecule) gene family: coding for a novel class of transmembrane proteins. Biochem. J. 357, 673–685 (2001).
Soboloff, J. et al. STIM2 is an inhibitor of STIM1-mediated store-operated Ca2+ entry. Curr. Biol. 16, 1465–1470 (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).
Vig, M. et al. CRACM1 is a plasma membrane protein essential for store-operated Ca2+ entry. Science 312, 1220–1223 (2006).
Prakriya, M. et al. Orai1 is an essential pore subunit of the CRAC channel. Nature 443, 230–233 (2006). References 80, 83 and 84 define ORAI1 as a component of the CRAC channel pore through site-directed mutagenesis of conserved glutamate residues, resulting in altered ion selectivity of the mutated CRAC channel.
Sather, W. A. & McCleskey, E. W. Permeation and selectivity in calcium channels. Annu. Rev. Physiol. 65, 133–159 (2003).
Owsianik, G., D'Hoedt, D., Voets, T. & Nilius, B. Structure-function relationship of the TRP channel superfamily. Rev. Physiol. Biochem. Pharmacol. 156, 61–90 (2006).
Yeromin, A. V. et al. Molecular identification of the CRAC channel by altered ion selectivity in a mutant of Orai. Nature 443, 226–229 (2006).
Vig, M. et al. CRACM1 multimers form the ion-selective pore of the CRAC channel. Curr. Biol. 16, 2073–2079 (2006).
Gwack, Y. et al. Biochemical and functional characterization of Orai family proteins. J. Biol. Chem. 282, 16232–16243 (2007).
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).
Lis, A. et al. CRACM1, CRACM2, and CRACM3 are store-operated Ca2+ channels with distinct functional properties. Curr. Biol. 17, 794–800 (2007).
Dehaven, W. I., Smyth, J. T., Boyles, R. R. & Putney, J. W. Jr. Calcium inhibition and calcium potentiation of Orai1, Orai2, and Orai3 calcium release-activated calcium channels. J. Biol. Chem. 282, 17548–17556 (2007).
Soboloff, J. et al. Orai1 and STIM reconstitute store-operated calcium channel function. J. Biol. Chem. 281, 20661–20665 (2006).
Peinelt, C. et al. Amplification of CRAC current by STIM1 and CRACM1 (Orai1). Nature Cell. Biol. 8, 771–773 (2006).
Fujimoto, M., Poe, J. C., Hasegawa, M. & Tedder, T. F. CD19 amplification of B lymphocyte Ca2+ responses: a role for Lyn sequestration in extinguishing negative regulation. J. Biol. Chem. 276, 44820–44827 (2001).
Tedder, T. F., Haas, K. M. & Poe, J. C. CD19–CD21 complex regulates an intrinsic Src family kinase amplification loop that links innate immunity with B-lymphocyte intracellular calcium responses. Biochem. Soc. Trans. 30, 807–811 (2002).
van Zelm, M. C. et al. An antibody-deficiency syndrome due to mutations in the CD19 gene. N. Engl. J. Med. 354, 1901–1912 (2006).
Otipoby, K. L. et al. CD22 regulates thymus-independent responses and the lifespan of B cells. Nature 384, 634–637 (1996).
O'Keefe, T. L., Williams, G. T., Davies, S. L. & Neuberger, M. S. Hyperresponsive B cells in CD22-deficient mice. Science 274, 798–801 (1996).
Sato, S. et al. CD22 is both a positive and negative regulator of B lymphocyte antigen receptor signal transduction: altered signaling in CD22-deficient mice. Immunity 5, 551–562 (1996).
Maeda, A., Kurosaki, M., Ono, M., Takai, T. & Kurosaki, T. Requirement of SH2-containing protein tyrosine phosphatases SHP-1 and SHP-2 for paired immunoglobulin-like receptor B (PIR-B)-mediated inhibitory signal. J. Exp. Med. 187, 1355–1360 (1998).
Blery, M. et al. The paired Ig-like receptor PIR-B is an inhibitory receptor that recruits the protein-tyrosine phosphatase SHP-1. Proc. Natl Acad. Sci. USA 95, 2446–2451 (1998).
Muta, T. et al. A 13-amino-acid motif in the cytoplasmic domain of FcγRIIB modulates B-cell receptor signalling. Nature 368, 70–73 (1994).
Maeda, A. et al. Paired immunoglobulin-like receptor B (PIR-B) inhibits BCR-induced activation of Syk and Btk by SHP-1. Oncogene 18, 2291–2297 (1999).
Bolland, S. & Ravetch, J. V. Spontaneous autoimmune disease in FcγRIIB-deficient mice results from strain-specific epistasis. Immunity 13, 277–285 (2000).
O'Keefe, T. L., Williams, G. T., Batista, F. D. & Neuberger, M. S. Deficiency in CD22, a B cell-specific inhibitory receptor, is sufficient to predispose to development of high affinity autoantibodies. J. Exp. Med. 189, 1307–1313 (1999).
Buckley, R. H. Molecular defects in human severe combined immunodeficiency and approaches to immune reconstitution. Annu. Rev. Immunol. 22, 625–655 (2004).
Notarangelo, L. et al. Primary immunodeficiency diseases: an update. J. Allergy Clin. Immunol. 114, 677–687 (2004).
Rawlings, D. J. Bruton's tyrosine kinase controls a sustained calcium signal essential for B lineage development and function. Clin. Immunol. 91, 243–253 (1999).
Takata, M. & Kurosaki, T. A role for Bruton's tyrosine kinase in B cell antigen receptor-mediated activation of phospholipase C-γ2. J. Exp. Med. 184, 31–40 (1996).
Fluckiger, A. C. et al. Btk/Tec kinases regulate sustained increases in intracellular Ca2+ following B-cell receptor activation. EMBO J. 17, 1973–1985 (1998).
Liu, K. Q., Bunnell, S. C., Gurniak, C. B. & Berg, L. J. T cell receptor-initiated calcium release is uncoupled from capacitative calcium entry in Itk-deficient T cells. J. Exp. Med. 187, 1721–1727 (1998).
Salzer, U. & Grimbacher, B. Common variable immunodeficiency: the power of co-stimulation. Semin. Immunol. 18, 337–346 (2006).
Carter, R. H. & Fearon, D. T. CD19: lowering the threshold for antigen receptor stimulation of B lymphocytes. Science 256, 105–107 (1992).
Wang, Y. & Carter, R. H. CD19 regulates B cell maturation, proliferation, and positive selection in the FDC zone of murine splenic germinal centers. Immunity 22, 749–761 (2005).
Fehr, T. et al. Antiviral protection and germinal center formation, but impaired B cell memory in the absence of CD19. J. Exp. Med. 188, 145–155 (1998).
Fischer, M. B. et al. A defect in the early phase of T-cell receptor-mediated T-cell activation in patients with common variable immunodeficiency. Blood 84, 4234–4241 (1994).
Bakowski, D., Glitsch, M. D. & Parekh, A. B. An examination of the secretion-like coupling model for the activation of the Ca2+ release-activated Ca2+ current ICRAC in RBL-1 cells. J. Physiol. 532, 55–71 (2001).
Simon, H. U., Mills, G. B., Hashimoto, S. & Siminovitch, K. A. Evidence for defective transmembrane signaling in B cells from patients with Wiskott–Aldrich syndrome. J. Clin. Invest. 90, 1396–1405 (1992).
Cianferoni, A. et al. Defective nuclear translocation of nuclear factor of activated T cells and extracellular signal-regulated kinase underlies deficient IL-2 gene expression in Wiskott–Aldrich syndrome. J. Allergy Clin. Immunol. 116, 1364–1371 (2005).
Huang, W., Ochs, H. D., Dupont, B. & Vyas, Y. M. The Wiskott–Aldrich syndrome protein regulates nuclear translocation of NFAT2 and NF-κB (RelA) independently of its role in filamentous actin polymerization and actin cytoskeletal rearrangement. J. Immunol. 174, 2602–2611 (2005).
Nolz, J. C. et al. The WAVE2 complex regulates actin cytoskeletal reorganization and CRAC-mediated calcium entry during T cell activation. Curr. Biol. 16, 24–34 (2006).
Pugh-Bernard, A. E. & Cambier, J. C. B cell receptor signaling in human systemic lupus erythematosus. Curr. Opin. Rheumatol. 18, 451–455 (2006).
Liossis, S. N., Kovacs, B., Dennis, G., Kammer, G. M. & Tsokos, G. C. B cells from patients with systemic lupus erythematosus display abnormal antigen receptor-mediated early signal transduction events. J. Clin. Invest. 98, 2549–2557 (1996).
Enyedy, E. J., Mitchell, J. P., Nambiar, M. P. & Tsokos, G. C. Defective FcγRIIb1 signaling contributes to enhanced calcium response in B cells from patients with systemic lupus erythematosus. Clin. Immunol. 101, 130–135 (2001).
Hippen, K. L. et al. FcγRIIB1 inhibition of BCR-mediated phosphoinositide hydrolysis and Ca2+ mobilization is integrated by CD19 dephosphorylation. Immunity 7, 49–58 (1997).
Shultz, L. D., Rajan, T. V. & Greiner, D. L. Severe defects in immunity and hematopoiesis caused by SHP-1 protein-tyrosine-phosphatase deficiency. Trends Biotechnol. 15, 302–307 (1997).
Hibbs, M. L. et al. Multiple defects in the immune system of Lyn-deficient mice, culminating in autoimmune disease. Cell 83, 301–311 (1995).
Yu, P. et al. Autoimmunity and inflammation due to a gain-of-function mutation in phospholipase Cγ2 that specifically increases external Ca2+ entry. Immunity 22, 451–465 (2005).
Sakaguchi, N. et al. Altered thymic T-cell selection due to a mutation of the ZAP-70 gene causes autoimmune arthritis in mice. Nature 426, 454–460 (2003).
Beeton, C. et al. Selective blockade of T lymphocyte K+ channels ameliorates experimental autoimmune encephalomyelitis, a model for multiple sclerosis. Proc. Natl Acad. Sci. USA 98, 13942–13947 (2001). This study describes the use of highly specific K+ channel blockers (reviewed in reference 131 ) for the inhibition of Ca2+ influx in T cells and the modulation of in vivo immune responses in EAE.
Reich, E. P. et al. Blocking ion channel KCNN4 alleviates the symptoms of experimental autoimmune encephalomyelitis in mice. Eur. J. Immunol. 35, 1027–1036 (2005).
Feske, S., Drager, R., Peter, H. H., Eichmann, K. & Rao, A. The duration of nuclear residence of NFAT determines the pattern of cytokine expression in human SCID T cells. J. Immunol. 165, 297–305 (2000).
Aramburu, J., Heitman, J. & Crabtree, G. R. Calcineurin: a central controller of signalling in eukaryotes. EMBO Rep. 5, 343–348 (2004).
Cahalan, M. D., Wulff, H. & Chandy, K. G. Molecular properties and physiological roles of ion channels in the immune system. J. Clin. Immunol. 21, 235–252 (2001).
Chandy, G. K. et al. K+ channels as targets for specific immunomodulation. Trends Pharmacol. Sci. 25, 280–289 (2004).
Bautista, D. M., Hoth, M. & Lewis, R. S. Enhancement of calcium signalling dynamics and stability by delayed modulation of the plasma-membrane calcium-ATPase in human T cells. J. Physiol. 541, 877–894 (2002).
Kirichok, Y., Krapivinsky, G. & Clapham, D. E. The mitochondrial calcium uniporter is a highly selective ion channel. Nature 427, 360–364 (2004).
Quintana, A. et al. Sustained activity of calcium release-activated calcium channels requires translocation of mitochondria to the plasma membrane. J. Biol. Chem. 281, 40302–40309 (2006).
Bierer, B. E., Hollander, G., Fruman, D. & Burakoff, S. J. Cyclosporin A and FK506: molecular mechanisms of immunosuppression and probes for transplantation biology. Curr. Opin. Immunol. 5, 763–773 (1993).
I wish to thank Drs M. Pipkin, M. Prakriya, K. Otipoby and A. Rao for critical reading of this manuscript and for many stimulating discussions. I apologize to those colleagues whose work I could not cite owing to space limitations. This work was supported by grant AI066128 from the National Institutes of Health, USA, and grants from the Charles H. Hood and March of Dimes Foundations.
Stefan Feske is one of the scientific founders of CalciMedica, a company that seeks to identify novel treatments for immune-related disorders.
- Immunological synapse
A large junctional structure that is formed at the cell surface between a T cell and an antigen-presenting cell (APC); it consists of molecules required for adhesion and signalling. This structure is important in establishing T-cell adhesion and polarity, is influenced by the cytoskeleton and transduces highly controlled secretory signals, thereby allowing the directed release of cytokines or lytic granules towards the APC or target cell.
(Nuclear factors of activated T cells). A family of transcription factors consisting of five members: NFAT1 (also known as NFATc2), NFAT2 (also known as NFATc1), NFAT3 (also known as NFATc4), NFAT4 (also known as NFATc3) and NFAT5 (also known as TonEBP). Except for NFAT5, all NFAT proteins are regulated by calcium signals. In addition to their role in T cells, NFAT proteins have regulatory roles in many organs, including the central nervous system, cardiovascular system, kidney, bone and skeletal muscle.
- Patch clamp
An electrophysiological technique to study ion channel currents in living cells. The electrode is a glass pipette, which forms a tight seal with the plasma membrane. Calcium-release-activated calcium channel currents are typically recorded in whole cell configuration from the entire cell.
- RNA interference
(RNAi). The use of double-stranded RNAs with sequences that precisely match a given gene, to 'knockdown' the expression of that gene by directing RNA-degrading enzymes to destroy the encoded mRNA transcript. RNAi is involved in innate immune responses, as well as in organ development, and has been exploited in large scale screens for genes regulating certain aspects of cell function.
- Severe combined immunodeficiency
(SCID). A primary (inherited) immunodeficiency characterized by defects in cell-mediated and humoral immune responses. Affected infants commonly die within 1 year due to recurrent infections. Mutations in about 10 different genes have been described, but defects in the common cytokine-receptor γ-chain are the most common form causing X-linked SCID. Other genes mutated in SCID include Janus kinase 3 (JAK3), recombination activating gene 1 (RAG1) and RAG2, IL-7 receptor α-chain (IL7R) and adenosine deaminase (ADA).
- TEC family
A family of non-receptor protein tyrosine kinases that contain a pleckstrin-homology domain. The prototype members are ITK (interleukin-2-inducible T-cell kinase) in T cells and BTK (Bruton's tyrosine kinase) in B cells. TEC-family kinases are involved in the intracellular signalling mechanisms of cytokine receptors, lymphocyte antigen receptors, heterotrimeric G-protein-coupled receptors and integrins.
- Immunoglobulin class switching
A region-specific recombination process that occurs in antigen-activated B cells. This occurs between switch-region DNA sequences and results in a change in the class of antibody that is produced — from IgM to either IgG, IgA or IgE. This imparts flexibility to the humoral immune response and allows it to exploit the different capacities of these antibody classes to activate the appropriate downstream effector mechanisms.
About this article
Cite this article
Feske, S. Calcium signalling in lymphocyte activation and disease. Nat Rev Immunol 7, 690–702 (2007). https://doi.org/10.1038/nri2152
2-Methoxyestradiol and its derivatives inhibit store-operated Ca2+ entry in T cells: Identification of a new and potent inhibitor
Biochimica et Biophysica Acta (BBA) - Molecular Cell Research (2021)
Inhibition of inflammatory cytokine production and proliferation in macrophages by Kunitz-type inhibitors from Echinococcus granulosus
Molecular and Biochemical Parasitology (2021)
Journal of Ethnopharmacology (2021)
The Journal of Clinical Endocrinology & Metabolism (2021)