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Calcium signalling in lymphocyte activation and disease

Key Points

  • 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.

Abstract

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.

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Figure 1: Store-operated calcium entry (SOCE) in T cells.
Figure 2: Domain architecture of the CRAC channel subunit ORAI1 and the Ca2+ sensor in the endoplasmic reticulum STIM1.
Figure 3: Redistribution of STIM1 following Ca2+ store depletion.
Figure 4: Mechanisms regulating Ca2+ levels in T cells.
Figure 5: The CRAC-channel–calcium–calcineurin–NFAT signalling pathway as a target for therapeutic immune modulation.

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Acknowledgements

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.

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Stefan Feske is one of the scientific founders of CalciMedica, a company that seeks to identify novel treatments for immune-related disorders.

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Glossary

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.

NFATs

(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.

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Feske, S. Calcium signalling in lymphocyte activation and disease. Nat Rev Immunol 7, 690–702 (2007). https://doi.org/10.1038/nri2152

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