Lymphocyte function is regulated by a network of different ion channels and transporters in the plasma membrane. These ion transport proteins modulate the cytoplasmic concentrations of cations, such as Ca2+, Mg2+ and Zn2+, which function as second messengers and thereby regulate gene expression, lymphocyte differentiation and effector functions.
The repertoire of ion channels in lymphocytes includes Ca2+ release-activated Ca2+ (CRAC) channels, P2X receptors, transient receptor potential (TRP) channels, K+ channels, Cl− channels, Mg2+ transporter protein 1 (MAGT1) and Zn2+ transporters of the ZIP and ZNT families.
CRAC channels composed of ORAI and stromal interaction molecule (STIM) proteins mediate store-operated Ca2+ entry (SOCE) in lymphocytes following antigen receptor engagement. ORAI1, ORAI2 and ORAI3 constitute the Ca2+-conducting pore of the CRAC channel, whereas STIM1 and STIM2 function as sensors of the Ca2+ concentration in the endoplasmic reticulum and activators of CRAC channels.
SOCE is the major pathway for increasing intracellular Ca2+ levels in lymphocytes. Inherited mutations of ORAI1 or STIM1 abolish Ca2+ influx in lymphocytes and result in a severe immunodeficiency syndrome termed CRAC channelopathy.
P2X receptors are Ca2+-permeable ion channels activated by extracellular ATP. Genetic deletion or inhibition of P2X receptors impairs T cell function.
The voltage-activated K+ channel KV1.3 and the Ca2+-activated K+ channel KCa3.1 regulate the membrane potential of lymphocytes and thereby provide the electrical driving force for the influx of divalent cations such as Ca2+. Inhibition of K+ channels has a profound effect on T cell activation.
Mg2+ channels and transporters (such as TRPM7 and MAGT1, respectively) regulate the influx of Mg2+ ions into T cells. Genetic deletion of TRPM7 and inherited mutations in MAGT1 impair T cell function and development.
Zn2+ transporters of the ZIP and ZNT families regulate Zn2+ uptake from the gut and Zn2+ levels in various tissues. In lymphocytes, several Zn2+ transporters have recently been reported to mediate Zn2+ signalling and T cell function, but the molecular regulation of these channels and their role in immunity remain to be defined.
Several Cl− channels are expressed by lymphocytes, including volume-activated Cl− channels, GABA (γ-aminobutyric acid) receptors and the cystic fibrosis transmembrane conductance regulator (CFTR). These roles of these proteins are currently not well understood in lymphocytes, but they have been implicated in the regulation of apoptosis, cytokine gene expression and T cell-mediated autoimmunity.
Inhibition of several ion channels in lymphocytes — such as CRAC channels, K+ channels and P2X receptors — modulates the severity of T cell-mediated autoimmunity and inflammation in animal models of disease, and inhibition of these channels is being explored as an approach to therapeutic immune modulation in patients.
Lymphocyte function is regulated by a network of ion channels and transporters in the plasma membrane of B and T cells. These proteins modulate the cytoplasmic concentrations of diverse cations, such as calcium, magnesium and zinc ions, which function as second messengers to regulate crucial lymphocyte effector functions, including cytokine production, differentiation and cytotoxicity. The repertoire of ion-conducting proteins includes calcium release-activated calcium (CRAC) channels, P2X receptors, transient receptor potential (TRP) channels, potassium channels, chloride channels and magnesium and zinc transporters. This Review discusses the roles of ion conduction pathways in lymphocyte function and immunity.
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We thank H. Wulff, B. N. Desai and H. McBride for their critical reading of the manuscript and their insightful comments. This work was supported in part by US National Institutes of Health grants AI066128 (to S.F.), NS057499 (to M.P.) and GM084195 (to E.Y.S.).
Stefan Feske is a co-founder and scientific adviser to CalciMedica, Inc.
- Ion channels
Pore-forming transmembrane proteins that enable the flow of ions down an electrochemical gradient.
- Ion transporters
Pore-forming transmembrane proteins that carry ions against a concentration gradient using energy, typically in the form of ATP.
- Ca2+ release-activated Ca2+ channels
(CRAC channels). Highly Ca2+-selective ion channels located in the plasma membrane that are encoded by ORAI proteins.
- Inositol-1,4,5-trisphosphate receptor
(InsP3 receptor). A Ca2+-permeable channel located in the membrane of the endoplasmic reticulum (ER) that mediates the release of Ca2+ from ER stores following binding by the second messenger InsP3.
- Ryanodine receptor
(RYR). A Ca2+-permeable channel located in the membrane of the sarcoplasmic reticulum (SR) and endoplasmic reticulum (ER) that mediates the release of Ca2+ from the SR or ER stores following binding by the second messenger cyclic ADP-ribose or Ca2+ itself.
- Sarcoplasmic/endoplasmic reticulum Ca2+ ATPases
(SERCAs). Ca2+ pumps located in the membrane of the endoplasmic reticulum (ER) that move Ca2+ from the cytoplasm into the ER through the hydrolysis of ATP.
- Plasma membrane Ca2+ ATPases
(PMCAs). A family of ion transport ATPases located in the plasma membrane that export Ca2+ from the cytoplasm.
- Store-operated Ca2+ entry
(SOCE). A Ca2+-influx process triggered by the depletion of endoplasmic reticulum Ca2+ stores and activation of plasma membrane ORAI Ca2+ channels by STIM proteins.
- Ion selectivity
The specificity of an ion channel for a particular species of ion, for example Ca2+, Mg2+, Na+ or K+. Non-selective channels do not discriminate between different types of ion.
A measure of the ability of an ion channel to carry electrical charge. The conductance is determined by dividing the electrical current by the potential difference (voltage) and is measured in siemens.
- Combined immunodeficiency
(CID). CID is caused by inherited defects in T cell function (but not T cell development). By contrast, severe CID (SCID) is caused by inherited defects in T cell (and in some cases B cell) development. SCID and CID result in severe (often lethal) infections in early infancy.
- Nuclear factor of activated T cells
(NFAT). A family of Ca2+-dependent transcription factors that are activated via dephosphorylation by the phosphatase calcineurin. They mediate the expression of many cytokine genes in lymphocytes.
- CRAC channelopathy
CRAC channel dysfunction caused by autosomal recessive mutations in ORAI1 and STIM1 that results in a pathognomonic clinical combination of immunodeficiency, autoimmunity, congenital muscular hypotonia and ectodermal dysplasia with impaired dental enamel calcification and sweat gland dysfunction.
- Membrane potential
The difference between the electrical potential inside and outside a cell. It is typically −60 to −80 mV in resting cells.
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Feske, S., Skolnik, E. & Prakriya, M. Ion channels and transporters in lymphocyte function and immunity. Nat Rev Immunol 12, 532–547 (2012). https://doi.org/10.1038/nri3233
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