T‐cell‐specific deletion of STIM1 and STIM2 protects mice from EAE by impairing the effector functions of Th1 and Th17 cells

Ma, Jian; McCarl, Christie-Ann; Khalil, Sara; Lüthy, Kevin; Feske, Stefan

doi:10.1002/eji.201040614

Cited by 111 publications

(125 citation statements)

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“…Moreover, genetic deletion of STIM1/2 ameliorates the disease course of EAE [30,31] and a human immunodeficiency syndrome associated with deficiencies in STIM1 function was described recently [32]. In summary, T cell activity involves a complex interplay of different ionic currents that regulate basic T cell effector functions like cytokine secretion and cell proliferation induced by T cell receptor stimulation.…”

Section: Calcium-release Activated Calcium Channels Cracmentioning

confidence: 99%

Ion channels in autoimmune neurodegeneration

et al. 2011

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a b s t r a c tMultiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system characterized by widespread inflammation, focal demyelination and a variable degree of axonal and neuronal loss. Ionic conductances regulate T cell activation as well as neuronal function and thus have been found to play a crucial role in MS pathogenesis. Since present therapeutical approaches are only partially effective so far, ion channel modulation as a future strategy was brought into focus. Here, we review the status quo concerning recent findings from ion channel research in MS and its animal model, experimental autoimmune encephalomyelitis.

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Section: Calcium-release Activated Calcium Channels Cracmentioning

confidence: 99%

Ion channels in autoimmune neurodegeneration

et al. 2011

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“…This defect in T cell proliferation was also observed in murine lymphocytes lacking both Stim1 and Stim2 genes, but not in murine T cells lacking only Stim1 or Orai1 gene function (Orai1 −/− or Orai1 knock-in (KI) mice, the latter expressing a nonfunctional ORAI1-R93W protein unable to mediate I CRAC ) (16,34,36). Additionally, effector cytokine production by CD4 + T cell subsets was almost completely absent in SOCEdeficient T cells (16,33,34,36,38). In accordance with a critical role for SOCE in T cell function not just in vitro but also in vivo, fully MHC mismatched skin allografts from BALB/c mice transplanted onto C57BL/6 mice were tolerated significantly longer by ORAI1-deficient than wildtype mice (36 (54), which is likely due to the significantly impaired effector T cell function in STIM1/STIM2-deficient but not scurfy mice.…”

Section: The Role Of Stim1 and Orai1 In Immune Cell Functionmentioning

confidence: 88%

“…SOCE in both human and murine CD4 + T cells is primarily mediated by STIM1 and ORAI1 following peptide-MHC binding by the TCR; in addition, binding of chemokines to their receptors can also trigger SOCE that requires STIM1 (11,16,(33)(34)(35)(36). While STIM1 mediates the fast activation of SOCE and the initial peak in [Ca 2+ ] i , STIM2 was shown to be required for maintaining sustained Ca 2+ influx following stimulation of CD4 + T cells (16).…”

Section: Effector Cd4 + T Cellsmentioning

confidence: 99%

“…STIM1-and ORAI1-deficient Th2 cells have reduced IL-4 and IL-10 production in vitro and accordingly Th2-mediated contact hypersensitivity was completely absent in Orai1 KI/KI mice (36). In the absence of SOCE, the production of IFN gamma and IL-2 by Th1 cells is decreased (16,33,34,36,38). Consequently, naive CD4 + T cells from STIM1-and ORAI1-deficient mice failed to induce inflammatory bowel disease (IBD) when transferred into lymphocytedeficient hosts in contrast to T cells from wildtype mice, which caused severe colitis in recipient animals (36).…”

Section: Effector Cd4 + T Cellsmentioning

confidence: 99%

“…This idea was further supported by the observation of Ca 2+ signals in immature lymphocytes (40, 41). As will be discussed in the next section, however, SOCE is not -at least not SOCE mediated by STIM1, STIM2 and ORAI1 proteins -required for T and B cell development (16,33,34,38,66). …”

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Physiological and pathophysiological functions of SOCE in the immune system

Feske¹

2012

Front Biosci

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Calcium signals play a critical role in many cell-type specific effector functions during innate and adaptive immune responses. The predominant mechanism to raise intracellular [Ca 2+ ] used by most immune cells is store-operated Ca 2+ entry (SOCE), whereby the depletion of endoplasmic reticulum (ER) Ca 2+ stores triggers the influx of extracellular Ca 2+ . SOCE in immune cells is mediated by the highly Ca 2+ selective Ca 2+ -release-activated Ca 2+ (CRAC) channel, encoded by ORAI1, ORAI2 and ORAI3 genes. ORAI proteins are activated by stromal interaction molecules (STIM) 1 and 2, which act as sensors of ER Ca 2+ store depletion. The importance of SOCE mediated by STIM and ORAI proteins for immune function is evident from the immunodeficiency and autoimmunity in patients with mutations in STIM1 and ORAI1 genes. These patients and studies in gene-targeted mice have revealed an essential role for ORAI/STIM proteins in the function of several immune cells. This review focuses on recent advances made towards understanding the role of SOCE in immune cells with an emphasis on the immune dysregulation that results from defects in SOCE in human patients and transgenic mice. KeywordsCalcium; Ca 2+ ; ORAI1; STIM1; STIM2; CRAC; SOCE; T cell; Lymphocyte; Macrophage; Neutrophil; Immunodeficiency; SCID; Review INTRODUCTION TO STORE-OPERATED CALCIUM ENTRY BY STIM AND ORAI PROTEINSThe spatio-temporal regulation of intracellular calcium (Ca 2+ ) concentrations [Ca 2+ ] i is an important, conserved mechanism of signal transduction used by virtually all cell types including cells of the immune system (1-5). The engagement of various immunoreceptors such as antigen receptors on lymphocytes, Fc receptors on mast cells and macrophages or chemokine receptors on neutrophils results in a rapid increase in [Ca 2+ ] i (2). This cytoplasmic Ca 2+ elevation can be supplied by two sources: the release of Ca 2+ from the endoplasmic reticulum (ER) or the influx of Ca 2+ from the extracellular space. The emptying of ER Ca 2+ stores is rapid but generally results in only a minor increase in [Ca 2+ ] i as the volume of the ER is small in most immune cells. However, following ER Ca 2+ store depletion, a secondary influx of extracellular Ca 2+ through highly selective Ca 2+ release activated Ca 2+ (CRAC) channels in the plasma membrane results in a more substantial and sustained increase in cytosolic Ca 2+ levels. This secondary Ca 2+ influx downstream of ER Ca 2+ stores is known as store-operated calcium entry (SOCE). Send correspondence to:Stefan Feske, Department of Pathology, New York University Medical Center, 550 First Avenue, SRB 316, New York, NY 10016, USA, Tel: 212-263-9066, Fax: 212-263-8211, feskes01@nyumc.org. NIH Public Access Author ManuscriptFront Biosci (Elite Ed). Author manuscript; available in PMC 2013 September 16. Published in final edited form as:Front Biosci (Elite Ed). ; 4: 2253-2268. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript SOCE was postulated in 1986 (6) and measured in pancre...

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Roles of Ion Transport in Control of Cell Motility

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Ludwig

Hanley

et al. 2013

Comprehensive Physiology

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Cell motility is an essential feature of life. It is essential for reproduction, propagation, embryonic development, and healing processes such as wound closure and a successful immune defense. If out of control, cell motility can become life-threatening as, for example, in metastasis or autoimmune diseases. Regardless of whether ciliary/flagellar or amoeboid movement, controlled motility always requires a concerted action of ion channels and transporters, cytoskeletal elements, and signaling cascades. Ion transport across the plasma membrane contributes to cell motility by affecting the membrane potential and voltage-sensitive ion channels, by inducing local volume changes with the help of aquaporins and by modulating cytosolic Ca(2+) and H(+) concentrations. Voltage-sensitive ion channels serve as voltage detectors in electric fields thus enabling galvanotaxis; local swelling facilitates the outgrowth of protrusions at the leading edge while local shrinkage accompanies the retraction of the cell rear; the cytosolic Ca(2+) concentration exerts its main effect on cytoskeletal dynamics via motor proteins such as myosin or dynein; and both, the intracellular and the extracellular H(+) concentration modulate cell migration and adhesion by tuning the activity of enzymes and signaling molecules in the cytosol as well as the activation state of adhesion molecules at the cell surface. In addition to the actual process of ion transport, both, channels and transporters contribute to cell migration by being part of focal adhesion complexes and/or physically interacting with components of the cytoskeleton. The present article provides an overview of how the numerous ion-transport mechanisms contribute to the various modes of cell motility.

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T‐cell‐specific deletion of STIM1 and STIM2 protects mice from EAE by impairing the effector functions of Th1 and Th17 cells

Cited by 111 publications

References 60 publications

Ion channels in autoimmune neurodegeneration

Ion channels in autoimmune neurodegeneration

Physiological and pathophysiological functions of SOCE in the immune system

Roles of Ion Transport in Control of Cell Motility

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