Article

Lymphocyte calcium signaling from membrane to nucleus

Department of Developmental Biology , Stanford University, Palo Alto, California, United States
Nature Immunology (Impact Factor: 20). 02/2006; 7(1):25-32. DOI: 10.1038/ni1295
Source: PubMed

ABSTRACT

Ca(2+) signals control a variety of lymphocyte responses, ranging from short-term cytoskeletal modifications to long-term changes in gene expression. The identification of molecules and channels that modulate Ca(2+) entry into T and B lymphocytes has both provided details of the molecular events leading to immune responses and raised controversy. Here we review studies of the pathways that allow Ca(2+) entry, the function of Ca(2+) in the regulation of cell polarity and motility and the principles by which Ca(2+)-dependent transcription regulates lymphocyte function.

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    • "Calcium ion entry across the plasma membrane is necessary for the initiation of T lymphocyte activation and proliferation following antigen encounter12345. A typical calcium response occurs in two distinct steps. Initially, calcium is released from the intracellular stores, like the ER[6], which then triggers extracellular calcium entry through store-operated calcium (SOC) channels in the plasma membrane[7,8]. "
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    ABSTRACT: The process of calcium entry in T cells is a multichannel and multi-step process. We have studied the requirement for L-type calcium channels (Cav1.1) α1S subunits during calcium entry after TCR stimulation. High expression levels of Cav1.1 channels were detected in activated T cells. Sequencing and cloning of Cav1.1 channel cDNA from T cells revealed that a single splice variant is expressed. This variant lacks exon 29, which encodes the linker region adjacent to the voltage sensor, but contains five new N-terminal exons that substitute for exons 1 and 2, which are found in the Cav1.1 muscle counterpart. Overexpression studies using cloned T cell Cav1.1 in 293HEK cells (that lack TCR) suggest that the gating of these channels was altered. Knockdown of Cav1.1 channels in T cells abrogated calcium entry after TCR stimulation, suggesting that Cav1.1 channels are controlled by TCR signaling.
    Full-text · Article · Jan 2016 · PLoS ONE
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    • "We used TLR2 knockdown PIE cells and calcium mobilization to evaluate the capability of L. plantarum N14 to modulate cytokines production in PIE cells. Calcium (Ca 2+ ) can be induced by variety of extracellular stimulants via TLRs and is essential for NF-␬B activation and gene expressions (Gallo et al., 2006; Chun and Prince, 2006). TLR2 ligands induce intracellular Ca 2+ mobilization in bone marrow derived macrophages and DCs (Aki et al., 2008). "
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    ABSTRACT: The radioprotective 105 (RP105)/MD1 complex is a member of the Toll-like receptor (TLR) family. It was reported that RP105/MD1 cooperates with the lipopolysaccharide (LPS) receptor TLR4/MD2 complex and plays a crucial role in the response of immune cells to LPS. This work evaluated whether RP105, TLR4 or TLR2 were involved in the immunoregulatory capacities of Lactobacillus plantarum N14 (LP14) or its exopolysaccharides (EPS). EPS from LP14 were fractionated into neutral (NPS) and acidic (APS) EPS by anion exchange chromatography. Experiments with transfectant HEKRP105/MD1 and HEKTLR2 cells demonstrated that LP14 strongly activated NF-κB via RP105 and TLR2. When we studied the capacity of APS to activate NF-κB pathway in HEKRP105/MD1 and HEKTLR4 cells; we observed that APS strongly stimulated both transfectant cells. Our results also showed that LP14 and APS were able to decrease the production of pro-inflammatory cytokines (IL-6, IL-8 and MCP-1) in porcine intestinal epithelial (PIE) cells in response to enterotoxigenic Escherichia coli (ETEC) challenge. In order to confirm the role of TLR2, TLR4 and RP105 in the immunoregulatory effect of APS from LP14, we used small interfering RNA (siRNA) to knockdown these receptors in PIE cells. The capacity of LP14 and APS to modulate pro-inflammatory cytokine expression was significantly reduced in PIERP105−/− cells. It was also shown that LP14 and APS were capable of upregulating negative regulators of the TLR signaling in PIE cells. This work describes for the first time that a Lactobacillus strain and its EPS reduce inflammation in intestinal epithelial cells in a RP105/MD1-dependend manner.
    Full-text · Article · Nov 2014 · Molecular Immunology
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    • "Upon accumulation, cytosolic calcium binds calmodulin (CaM), inducing a conformational change in CaM that promotes its ability to interact with and activate the protein phosphatase calcineurin (65). Calcineurin dephosphorylates the cytoplasmic subunits (NFATc) of nuclear factor of activated T cells (NFAT) transcription complexes, exposing a nuclear localization sequence that results in their import into the nucleus (66). "
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    ABSTRACT: As a vital second messenger in the activation of lymphocytes, the divalent cation Ca(2+) plays numerous roles in adaptive immune responses. Importantly, Ca(2+) signaling is essential for T cell activation, tolerance of self-antigens, and homeostasis. Supporting the essential role of Ca(2+) signaling in T cell biology, the Ca(2+) regulated protein phosphatase calcineurin is a key target of pharmacologic inhibition for preventing allograft rejection and for autoimmune therapy. Recent studies have highlighted the unique role of Stim1 and Orai1/2 proteins in the regulation of store-operated/calcium release activated calcium (CRAC) channels in the context of T cells. While Ca(2+) is known to modulate T cell activation via effects on calcineurin and its target, nuclear factor of activated T cells (NFAT), this second messenger also regulates other pathways, including protein kinase C, calmodulin kinases, and cytoskeletal proteins. Ca(2+) also modulates the unique metabolic changes that occur during in distinct T cell stages and subsets. Herein, we discuss the means by which Ca(2+) mobilization modulates cellular metabolism following T cell receptor ligation. Further, we highlight the crosstalk between mitochondrial metabolism, reactive oxygen species (ROS) generation, and CRAC channel activity. As a target of mitochondrial ROS and Ca(2+) regulation, we describe the involvement of the serine/threonine kinase DRAK2 in the context of these processes. Given the important roles for Ca(2+) dependent signaling and cellular metabolism in adaptive immune responses, the crosstalk between these pathways is likely to be important for the regulation of T cell activation, tolerance, and homeostasis.
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