Lymphocyte calcium signaling from membrane to nucleus

Gallo, Elena; Canté-Barrett, Kirsten; Crabtree, Gerald R.

doi:10.1038/ni1295

Cited by 164 publications

(132 citation statements)

References 165 publications

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“…InsP 3 releases Ca 2+ from internal Ca 2+ stores and the Ca 2+ store depletion activates store-operated Ca 2+ channels called Ca 2+ release-activated Ca 2+ (CRAC)/ORAI channels in T cells [7,8]. There is no doubt that Ca 2+ signaling is required for clonal expansion (proliferation) of T cells as well as for the generation and activation of effector cells [9][10][11]. There is also clear evidence that CRAC channels provide the only pathway for Ca 2+ entry in T cells [12,13].…”

Section: Introductionmentioning

confidence: 99%

Calcium dependence of T cell proliferation following focal stimulation

et al. 2007

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Clonal T cell expansion through proliferation is a central process of the adaptive immune response. Apoptosis of activated T cells is required to avoid chronic inflammation. T cell proliferation and apoptosis are often analyzed with stimuli that do not induce formation of a functional immunological synapse. Here we analyze the Ca 2+ dependence of proliferation and apoptosis in primary human CD4 + T cells following stimulation with anti-CD3/anti-CD28-coated beads, which induce a tight interaction similar to the immunological synapse. We found this focal stimulation to be much more efficient for stimulating IL-2 production and proliferation than non-focal TCR stimuli. Surprising little Ca 2+ entry through Ca 2+ channels was required for T cell proliferation. Transient free intracellular calcium concentration ([Ca 2+ ] i ) elevations of up to 220 nM from a baseline level of around 40 nM were sufficient for maximal proliferation in primary human CD4 + T cells. We also show that proliferation was very Ca 2+ sensitive in the range 90-120 nM, whereas apoptosis was basically constant for [Ca 2+ ] i levels of 90-120 nM. We conclude that very small changes in [Ca 2+ ] i can dramatically change the ratio between proliferation and apoptosis, thus keeping the balance between overshooting and inefficient immune responses.

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Section: Introductionmentioning

confidence: 99%

Calcium dependence of T cell proliferation following focal stimulation

et al. 2007

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“…Two stages of calcium mobilization have been distinguished in lymphocytes and other nonexcitable cells (3)(4)(5). The first stage involves activation of phospholipase C by trimeric G protein-or tyrosine kinase-coupled receptors.…”

mentioning

confidence: 99%

Coupling of STIM1 to store-operated Ca ²⁺ entry through its constitutive and inducible movement in the endoplasmic reticulum

Baba¹,

Hayashi

Fujii³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

296

316

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Depletion of intracellular calcium (Ca 2؉ ) stores induces storeoperated Ca 2؉ (SOC) entry across the plasma membrane (PM). STIM1, a putative Ca 2؉ sensor in the endoplasmic reticulum (ER), has been recently shown to be necessary for SOC channel activation. Here we show that STIM1 dynamically moves in tubulovesicular shape on the ER and its subcompartment in resting living cells, whereas, upon Ca 2؉ store depletion, it is rapidly redistributed into discrete puncta that are located underneath, but not inserted into the PM. Normal constitutive movement of STIM1 is mediated through the coiled-coil and Ser͞Thr-rich C-terminal domains in the cytoplasmic region of STIM1, whereas subsequent inducible puncta formation further requires the sterile ␣ motif domain protruding into the ER lumen. Each of these three domains (coiled-coil, Ser͞Thr-rich, and sterile ␣ motif) was essential for activating SOC channels. Hence, our findings based on structure-function experiments suggest that constitutive dynamic movement of STIM1 in the ER and its subcompartment is obligatory for subsequent depletion-dependent redistribution of STIM1 into puncta underneath the PM and activation of SOC channels.B cell receptor ͉ calcium signaling ͉ DT40 ͉ store-operated calcium C ytosolic Ca 2ϩ signals are a key to the regulation of various physiological events (1, 2). Two stages of calcium mobilization have been distinguished in lymphocytes and other nonexcitable cells (3-5). The first stage involves activation of phospholipase C by trimeric G protein-or tyrosine kinase-coupled receptors. This enzyme hydrolyzes phosphatidylinositol bisphosphate to release the second messenger inositol-1,4,5-trisphosphate, which binds to its receptor in the endoplasmic reticulum (ER) membrane, thereby causing rapid but transient release of Ca 2ϩ from ER stores. The second stage involves a sustained influx of extracellular Ca 2ϩ across the plasma membrane (PM) in a process termed store-operated Ca 2ϩ (SOC) entry. In this process, depletion of Ca 2ϩ within the ER lumen serves as the primary trigger to open SOC channels residing in the PM.STIM1 has recently emerged to play a critical role in coupling the first and second stages of calcium mobilization (6, 7). The STIM1 protein is thought to function primarily as a sensor of Ca 2ϩ within the ER stores, because a single N-terminal EF-hand Ca 2ϩ binding motif is located within the ER lumen (7,8). The activation mechanism of STIM1, however, has remained elusive. For instance, Zhang and colleagues (9, 10) proposed that insertion of STIM1 from the ER to the PM, presumably through vesicular transport, would be a prerequisite for subsequent SOC channel activation. Furthermore, STIM1 in the PM has been reported to play a role for SOC activation (11). But others have shown that STIM1 redistributed into puncta near the PM without inserting into the PM and proposed that this aggregated STIM1 might activate SOC channels (7, 12).To elucidate the mechanisms by which STIM1 activates SOC channels, we have constructed STIM1 mutants and ...

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“…CD22 null mice possess hyperresponsive B cells (4), illustrating a role for CD22 in establishing a threshold for B cell activation. Specifically, an increase in intracellular Ca 2ϩ ion concentration is a hallmark of B cell activation (5,6), and B cells isolated from CD22 null mice display increased Ca 2ϩ flux in response to antigen (4,7). Thus, loss of CD22 results in a lowering of the threshold for B cell activation.…”

mentioning

confidence: 99%

Sialylated multivalent antigens engage CD22in transand inhibit B cell activation

Courtney¹,

Puffer²,

Pontrello

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

118

178

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CD22 is an inhibitory coreceptor on the surface of B cells that attenuates B cell antigen receptor (BCR) signaling and, therefore, B cell activation. Elucidating the molecular mechanisms underlying the inhibitory activity of CD22 is complicated by the ubiquity of CD22 ligands. Although antigens can display CD22 ligands, the receptor is known to bind to sialylated glycoproteins on the cell surface. The propinquity of CD22 and cell-surface glycoprotein ligands has led to the conclusion that the inhibitory properties of the receptor are due to cis interactions. Here, we examine the functional consequences of trans interactions by employing sialylated multivalent antigens that can engage both CD22 and the BCR. Exposure of B cells to sialylated antigens results in the inhibition of key steps in BCR signaling. These results reveal that antigens bearing CD22 ligands are powerful suppressors of B cell activation. The ability of sialylated antigens to inhibit BCR signaling through trans CD22 interactions reveals a previously unrecognized role for the Siglec-family of receptors as modulators of immune signaling.B cell antigen receptor ͉ multivalency ͉ sialic acid ͉ siglec ͉ autoimmunity T he initiation of an immune response or the prevention of autoimmunity depends upon the ability of the B cell antigen receptor (BCR) to transmit signals that positively or negatively regulate B lymphocyte survival, proliferation, and differentiation (1). To avoid detrimental autoimmune responses, a means of differentiating between foreign and self-antigens is required; coreceptors that modulate BCR signaling can ensure that these distinctions are made. CD22 is an inhibitory coreceptor that can attenuate BCR signaling (2, 3). CD22 null mice possess hyperresponsive B cells (4), illustrating a role for CD22 in establishing a threshold for B cell activation. Specifically, an increase in intracellular Ca 2ϩ ion concentration is a hallmark of B cell activation (5, 6), and B cells isolated from CD22 null mice display increased Ca 2ϩ flux in response to antigen (4, 7). Thus, loss of CD22 results in a lowering of the threshold for B cell activation. Other data also support this conclusion: CD22 null mice exhibit increased serum IgM concentrations, decreased surface IgM levels on peripheral B cells, increased induction of apoptosis in response to BCR crosslinking, and increased serum autoantibody titers (8). These observations are consistent with the loss of CD22 leading to increased sensitivity and chronic B cell activation.The process of B cell activation ensues upon binding of multivalent antigen to the BCR. Antigen-induced clustering elicits phosphorylation of the cytoplasmic immunoreceptor tyrosinebased activation motifs (ITAMs), which are present in the BCRassociated signaling proteins Ig␣/␤. The phosphorylation reaction is catalyzed by Src-family kinases such as Lyn. Upon phosphorylation of the BCR components, Syk kinase is recruited to the BCR signaling complex (9). Syk is essential for propagating BCR signaling (10, 11). It acts along with...

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Lymphocyte calcium signaling from membrane to nucleus

Cited by 164 publications

References 165 publications

Calcium dependence of T cell proliferation following focal stimulation

Calcium dependence of T cell proliferation following focal stimulation

Coupling of STIM1 to store-operated Ca ²⁺ entry through its constitutive and inducible movement in the endoplasmic reticulum

Sialylated multivalent antigens engage CD22in transand inhibit B cell activation

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Lymphocyte calcium signaling from membrane to nucleus

Cited by 164 publications

References 165 publications

Calcium dependence of T cell proliferation following focal stimulation

Calcium dependence of T cell proliferation following focal stimulation

Coupling of STIM1 to store-operated Ca 2+ entry through its constitutive and inducible movement in the endoplasmic reticulum

Sialylated multivalent antigens engage CD22in transand inhibit B cell activation

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Coupling of STIM1 to store-operated Ca ²⁺ entry through its constitutive and inducible movement in the endoplasmic reticulum