Tweeters, Woofers and Horns: The Complex Orchestration of Calcium Currents in T Lymphocytes

Nohara, Lilian L.; Stanwood, Shawna R.; Omilusik, Kyla; Jefferies, Wilfred A.

doi:10.3389/fimmu.2015.00234

Cited by 40 publications

(41 citation statements)

References 122 publications

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“…Typically TCR engagement which triggers the canonical pathway results in depletion of endoplasmic reticulum (ER) Ca 2+ stores and subsequent sustained influx of extracellular Ca 2+ through Ca 2+ release-activated Ca 2+ (CRAC) channels in the plasma membrane (16). Since elevation of intracellular Ca2+ levels is a vital event that mediates T cell activation, we examined the ability of T cells to flux calcium following stimulation by the analog peptide A9 presented by I-A q .…”

Section: Resultsmentioning

confidence: 99%

“…Another early step in the pathway following TCR engagement is the cleaving of phosphatidylinositol 4,5-bisphosphate (PIP2) from plasma membrane phospholipids to generate diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3) (11, 16). We know that A9 can activate Syk but whether Syk activation invariably leads to phosphatidylinositol turnover is unknown.…”

Section: Resultsmentioning

confidence: 99%

“…In T cells, elevation of intracellular Ca2+ levels is another vital event that mediates T cell activation, proliferation, development, differentiation, homeostasis, effector function, and cell death (16). The mechanisms that regulate intracellular Ca 2+ signaling in lymphocytes involve tightly controlled concinnity of multiple ion channels, membrane receptors, and signaling molecules.…”

Section: Discussionmentioning

confidence: 99%

“…DAG, along with Ca 2+ , activates protein kinase C (PKC). IP3 binds to IP3 receptors (IP3R) in the endoplasmic reticulum (ER), leading to the release of Ca 2+ from the ER intracellular stores into the cytoplasm (16). Our data clearly demonstrate that this pathway is functional in the alternate signaling pathway and that FcRγ is required for the calcium flux to occur.…”

Section: Discussionmentioning

confidence: 99%

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Characterization of the Syk-Dependent T Cell Signaling Response to an Altered Peptide

Park

Rotondo

Cullins

et al. 2016

The Journal of Immunology

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Rheumatoid Arthritis (RA) is an autoimmune disorder characterized by T cell dysregulation. We have shown that an altered peptide ligand (A9) activates T cells to utilize an alternate signaling pathway which is dependent upon FcRγ and Syk, resulting in downregulation of inflammation. In the experiments described herein we have attempted to determine the molecular basis of this paradox. Three major SFKs found in T cells (Lck, Fyn, and Lyn) were tested for activation following stimulation by A9/I-Aq. Unexpectedly we found they are not required for T cell functions induced by A9/I-Aq, nor are they required for APL stimulation of cytokines. On the other hand, the induction of the second messenger inositol trisphosphate (IP3) and the mobilization of calcium are clearly triggered by the APL A9/I-Aq stimulation and are required for cytokine production albeit the cytokines induced are different from those produced after activation of the canonical pathway. DBA/1 mice doubly deficient in both IL-4 and IL-10 were used to confirm that these two cytokines are important for the APL-induced attenuation of arthritis. These studies provide a basis for exploring the effectiveness of analog peptides and the inhibitory T cells they induce as therapeutic tools for autoimmune arthritis.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Characterization of the Syk-Dependent T Cell Signaling Response to an Altered Peptide

Park

Rotondo

Cullins

et al. 2016

The Journal of Immunology

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“…One particular ion channel, the Ca 2+ release-activated Ca 2+ (CRAC) channel has been described as the major player in mediating SOCE in T cells [8, 11]. However, several additional families of ion channels are expressed at the plasma membrane of T cells and may therefore contribute to the regulation of Ca 2+ entry in T cells [12-14]. Thus, before the discovery of ORAI1 as the pore-forming plasma membrane subunit of the CRAC channel [8, 11], several members of the TRP channel family (e.g., TRPC1/3, TRPV6) were considered as candidates to form the CRAC channel.…”

Section: Introductionmentioning

confidence: 99%

Transient Receptor Potential (TRP) channels in T cells

Bertin

2015

Semin Immunopathol

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The Transient Receptor Potential (TRP) family of ion channels is widely expressed in many cell types and plays various physiological roles. Growing evidence suggests that certain TRP channels are functionally expressed in the immune system. Indeed, an increasing number of reports have demonstrated the functional expression of several TRP channels in innate and adaptive immune cells and have highlighted their critical role in the activation and function of these cells. However, very few reviews have been entirely dedicated to this subject. Here, we will summarize the recent findings with regards to TRP channel expression in T cells and discuss their emerging role as regulators of T cell activation and functions. Moreover, these studies suggest that beyond their pharmaceutical interest in pain management, certain TRP channels may represent potential novel therapeutic targets for various immune-related diseases.

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TRPM8 channel augments T‐cell activation and proliferation

Acharya

Tiwari

Majhi

et al. 2020

Cell Biology International

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The transient receptor potential melastatin 8 (TRPM8) is an ion channel that has been widely studied as a cold‐sensitive nociceptor. However, its importance in nonneuronal cells is mostly unexplored. Here, we describe the presence and functional significance of endogenous TRPM8, a nonselective Ca2+‐channel in T cell functions. The major pool of TRPM8 resides at the T cell surface and its surface accumulation significantly increases in activated T cells. TRPM8 activation synergizes with T‐cell receptor (TCR) stimulation to increase CD25, CD69 levels and enhances secretion of proinflammatory cytokine tumor necrosis factor. However, TRPM8 inhibition does not restrict TCR stimulation mediated activation of T cells, indicating that unlike the heat‐sensitive TRPV1 and TRPV4 channels, the cold‐sensitive TRPM8 channel may be dispensable during T‐cell activation, at least in mice. In this study, we demonstrate that TRPM8 promotes TCR‐induced intracellular calcium increase. TRPM8 activation is beneficial for T‐cell activation and differentiation into effector cells. TRPM8 inhibition during the T‐cell activation process may lead to altered phenotype and reduced proliferation, without affecting cell viability. These results collectively establish TRPM8 as a functional calcium channel whose activation may be utilized for mounting an effective immune response. The findings of this study will be relevant to the regulation and response of T cells during cell‐mediated immunity. These results will likely further our understanding on the role of ion channels in T‐cell activation.

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Tweeters, Woofers and Horns: The Complex Orchestration of Calcium Currents in T Lymphocytes

Cited by 40 publications

References 122 publications

Characterization of the Syk-Dependent T Cell Signaling Response to an Altered Peptide

Characterization of the Syk-Dependent T Cell Signaling Response to an Altered Peptide

Transient Receptor Potential (TRP) channels in T cells

TRPM8 channel augments T‐cell activation and proliferation

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