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Nuclear factor of activated T cells (NFAT) was first described almost three decades ago as a Ca 2+ /calcineurin-regulated transcription factor in T cells. Since then, a large body of research uncovered the regulation and physiological function of different NFAT homologues in the immune system and many other tissues. In this review, we will discuss novel roles of NFAT in T cells, focusing mainly on its function in humoral immune responses, immunological tolerance, and the regulation of immune metabolism.

Key Points 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 Ca 2+ , Mg 2+ and Zn 2+ , which function as second messengers and thereby regulate gene expression, lymphocyte differentiation and effector functions. The repertoire of ion channels in lymphocytes includes Ca 2+ release-activated Ca 2+ (CRAC) channels, P2X receptors, transient receptor potential (TRP) channels, K + channels, Cl − channels, Mg 2+ transporter protein 1 (MAGT1) and Zn 2+ transporters of the ZIP and ZNT families. CRAC channels composed of ORAI and stromal interaction molecule (STIM) proteins mediate store-operated Ca 2+ entry (SOCE) in lymphocytes following antigen receptor engagement. ORAI1, ORAI2 and ORAI3 constitute the Ca 2+ -conducting pore of the CRAC channel, whereas STIM1 and STIM2 function as sensors of the Ca 2+ concentration in the endoplasmic reticulum and activators of CRAC channels. SOCE is the major pathway for increasing intracellular Ca 2+ levels in lymphocytes. Inherited mutations of ORAI1 or STIM1 abolish Ca 2+ influx in lymphocytes and result in a severe immunodeficiency syndrome termed CRAC channelopathy. P2X receptors are Ca 2+ -permeable ion channels activated by extracellular ATP. Genetic deletion or inhibition of P2X receptors impairs T cell function. The voltage-activated K + channel K V 1.3 and the Ca 2+ -activated K + channel K Ca 3.1 regulate the membrane potential of lymphocytes and thereby provide the electrical driving force for the influx of divalent cations such as Ca 2+ . Inhibition of K + channels has a profound effect on T cell activation. Mg 2+ channels and transporters (such as TRPM7 and MAGT1, respectively) regulate the influx of Mg 2+ ions into T cells. Genetic deletion of TRPM7 and inherited mutations in MAGT1 impair T cell function and development. Zn 2+ transporters of the ZIP and ZNT families regulate Zn 2+ uptake from the gut and Zn 2+ levels in various tissues. In lymphocytes, several Zn 2+ transporters have recently been reported to mediate Zn 2+ 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. Ion channels and transporters, by modulating cytoplasmic concentrations of various cations, control key lymphocyte effector functions. Here, the authors review the roles of these proteins in lymphocytes and how they might interact to fine-tune cell responses. 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.

Store-operated Ca 2+ entry (SOCE) through Ca 2+ release-activated Ca 2+ (CRAC) channels is critical for lymphocyte function and immune responses. CRAC channels are hexamers of ORAI proteins that form the channel pore, but the contributions of individual ORAI homologues to CRAC channel function are not well understood. Here we show that deletion of Orai1 reduces, whereas deletion of Orai2 increases, SOCE in mouse T cells. These distinct effects are due to the ability of ORAI2 to form heteromeric channels with ORAI1 and to attenuate CRAC channel function. The combined deletion of Orai1 and Orai2 abolishes SOCE and strongly impairs T cell function. In vivo , Orai1/Orai2 double-deficient mice have impaired T cell-dependent antiviral immune responses, and are protected from T cell-mediated autoimmunity and alloimmunity in models of colitis and graft-versus-host disease. Our study demonstrates that ORAI1 and ORAI2 form heteromeric CRAC channels, in which ORAI2 fine-tunes the magnitude of SOCE to modulate immune responses. Ca 2+ release-activated Ca 2+ (CRAC) channels are essential for protective immunity, but the immunological functions of the three ORAI homologues that form CRAC channels are unclear. Here the authors show that ORAI1 and ORAI2 form heteromeric CRAC channels, which fine-tune T cell activation and immune responses.

Ion channels, exchangers and pumps are expressed ubiquitously in cells from all phyla of life. In mammals, their role is best described in excitable cells, where they regulate the initiation and propagation of action potentials. There are over 70 different types of K + channels subunits that contribute to these processes. In non-excitable cells, K + channels set the resting membrane potential, which in turn drives the activity of other translocators. K + channels also help maintain cell volume, influence cell proliferation and apoptosis and regulate Ca 2+ signaling, which in turn is crucial for many cellular processes, including metabolism, secretion, and gene expression. K + channels play crucial roles in the activation, proliferation and a variety of other functions in cells of the innate and adaptive immune system. The ATP-sensitive K + (K ATP ) channel has an established role in diverse cells, but its presence and function in immunity is scantly described. Public gene expression databases show that K ATP channel subunits are highly expressed in NKT and NK cells, and that they are significantly upregulated after infection in CD8+ T cells and macrophages. We discuss these findings in the light of the available literature and propose a role for K ATP channels in cytotoxicity of cells that are primed for a rapid immune response. Possible underlying molecular mechanisms are discussed.

Calcium pump Two groups report the molecular identification of the long-sought CRAC channel as a plasma membrane protein known variously as olf186-F, Orai and CRACM1. The CRAC channel is of fundamental importance to Ca 2+ signalling mechanisms in cell biology. Experimental results suggest an alternative mode for stimulation of Atm by double-strand breaks, in which Atm autophosphorylation at Ser 1987 (like trans-phosphorylation of downstream substrates) is a consequence rather than a cause of Atm activation. Stimulation of immune cells causes depletion of Ca 2+ from endoplasmic reticulum (ER) stores, thereby triggering sustained Ca 2+ entry through store-operated Ca 2+ release-activated Ca 2+ (CRAC) channels, an essential signal for lymphocyte activation and proliferation 1 , 2 . Recent evidence indicates that activation of CRAC current is initiated by STIM proteins, which sense ER Ca 2+ levels through an EF-hand located in the ER lumen and relocalize upon store depletion into puncta closely associated with the plasma membrane 3 , 4 , 5 . We and others recently identified Drosophila Orai and human Orai1 (also called TMEM142A) as critical components of store-operated Ca 2+ entry downstream of STIM 6 , 7 , 8 . Combined overexpression of Orai and Stim in Drosophila cells 8 , or Orai1 and STIM1 in mammalian cells 9 , 10 , 11 , leads to a marked increase in CRAC current. However, these experiments did not establish whether Orai is an essential intracellular link between STIM and the CRAC channel, an accessory protein in the plasma membrane, or an actual pore subunit. Here we show that Orai1 is a plasma membrane protein, and that CRAC channel function is sensitive to mutation of two conserved acidic residues in the transmembrane segments. E106D and E190Q substitutions in transmembrane helices 1 and 3, respectively, diminish Ca 2+ influx, increase current carried by monovalent cations, and render the channel permeable to Cs + . These changes in ion selectivity provide strong evidence that Orai1 is a pore subunit of the CRAC channel.

It is widely assumed that inositol trisphosphate (IP 3 ) and ryanodine (Ry) receptors share the same Ca 2+ pool in central mammalian neurons. We now demonstrate that in hippocampal CA1 pyramidal neurons IP 3 - and Ry-receptors are associated with two functionally distinct intracellular Ca 2+ stores, respectively. While the IP 3 -sensitive Ca 2+ store refilling requires Orai2 channels, Ry-sensitive Ca 2+ store refilling involves voltage-gated Ca 2+ channels (VGCCs). Our findings have direct implications for the understanding of function and plasticity in these central mammalian neurons. It is generally assumed, from previous studies in cerebellar Purkinje neurons, that IP 3 and Ry receptors share the same intracellular Ca 2+ pool. In this study, the authors demonstrate the existence of two functionally distinct Ca 2+ stores in mouse CA1 pyramidal neurons by showing that refilling of IP 3 -sensitive stores relies on Orai2 channels, whereas Ry-sensitive stores involve VGCCs for spontaneous store refilling

T regulatory (Treg) cells maintain immunological tolerance and organ homeostasis. Activated Treg cells differentiate into effector Treg subsets that acquire tissue-specific functions. Ca 2+ influx via Ca 2+ release-activated Ca 2+ (CRAC) channels formed by STIM and ORAI proteins is required for the thymic development of Treg cells, but its function in mature Treg cells remains unclear. Here we show that deletion of Stim1 and Stim2 genes in mature Treg cells abolishes Ca 2+ signaling and prevents their differentiation into follicular Treg and tissue-resident Treg cells. Transcriptional profiling of STIM1/STIM2-deficient Treg cells reveals that Ca 2+ signaling regulates transcription factors and signaling pathways that control the identity and effector differentiation of Treg cells. In the absence of STIM1/STIM2 in Treg cells, mice develop a broad spectrum of autoantibodies and fatal multiorgan inflammation. Our findings establish a critical role of CRAC channels in controlling lineage identity and effector functions of Treg cells. Regulatory T (Treg) cells are important for maintaining immune homeostasis. Here the authors show that STIM1 and STIM2, which activate the Ca 2+ channel ORAI1, are essential for the differentiation of peripheral Treg cells into tissue-resident and follicular Treg cells and their ability to limit autoimmunity in mice.

The binding of stromal interaction molecule 1 (STIM1) to ORAI calcium channels is critical for store-operated calcium entry (SOCE), a calcium influx pathway conserved among nearly all vertebrate cells. Although many major steps of this pathway are well understood, crucial details regarding the mechanism of STIM1 activation remain unclear. A study in this issue provides important new insights into the conformational changes that occur during STIM1 activation.

Store-operated Ca 2 + entry (SOCE) is an important Ca 2+ influx pathway in many non-excitable and some excitable cells. It is regulated by the filling state of intracellular Ca 2+ stores, notably the endoplasmic reticulum (ER). Reduction in [Ca 2+ ] ER results in activation of plasma membrane Ca 2+ channels that mediate sustained Ca 2+ influx which is required for many cell functions as well as refilling of Ca 2+ stores. The Ca 2+ release activated Ca 2+ (CRAC) channel is the best characterized SOC channel with well-defined electrophysiological properties. In recent years, the molecular components of the CRAC channel, long mysterious, have been defined. ORAI1 (or CRACM1) acts as the pore-forming subunit of the CRAC channel in the plasma membrane. Stromal interaction molecule (STIM) 1 is localized in the ER, senses [Ca 2+ ] ER , and activates the CRAC channel upon store depletion by binding to ORAI1. Both proteins are widely expressed in many tissues in both human and mouse consistent with the widespread prevalence of SOCE and CRAC channel currents in many cells types. CRAC channelopathies in human patients with mutations in STIM1 and ORAI1 are characterized by abolished CRAC channel currents, lack of SOCE and—clinically—immunodeficiency, congenital myopathy, and anhydrotic ectodermal dysplasia. This article reviews the role of ORAI and STIM proteins for SOCE and CRAC channel function in a variety of cell types and tissues and compares the phenotypes of ORAI1 and STIM1-deficient human patients and mice with targeted deletion of Orai and Stim genes.

Store‐operated calcium entry (SOCE) through Ca 2+ release‐activated Ca 2+ (CRAC) channels regulates the function of many immune cells. Patients with loss‐of‐function mutations in the CRAC channel genes ORAI1 or STIM1 are immunodeficient and are prone to develop virus‐associated tumours. This and the reported role of Ca 2+ signals in cytotoxic lymphocyte function suggest that SOCE may be critical for tumour immune surveillance. Using conditional knock out mice lacking STIM1 and its homologue STIM2, we find that SOCE in CD8 + T cells is required to prevent the engraftment of melanoma and colon carcinoma cells and to control tumour growth. SOCE is essential for the cytotoxic function of CTLs both in vivo and in vitro by regulating the degranulation of CTLs, their expression of Fas ligand and production of TNF‐α and IFN‐γ. Our results emphasize an important role of SOCE in antitumour immunity, which is significant given recent reports arguing in favour of CRAC channel inhibition for cancer therapy. Graphical Abstract Cytotoxic lymphocytes are critical for antitumor immunity. Here, store operated calcium entry (SOCE) mediated by STIM1 and ‐2 is shown essential to CD8 + T cells antitumor immune responses, arguing against the use of drugs inhibiting SOCE.