scholarly journals A function for tyrosine phosphorylation of type 1 inositol 1,4,5-trisphosphate receptor in lymphocyte activation

2007 ◽  
Vol 179 (5) ◽  
pp. 923-934 ◽  
Author(s):  
Nikhil deSouza ◽  
Jie Cui ◽  
Miroslav Dura ◽  
Thomas V. McDonald ◽  
Andrew R. Marks
Keyword(s):  
T Cells ◽  
Tyrosine Phosphorylation ◽  
Lymphocyte Activation ◽  
Cell Receptor ◽  
Scaffolding Protein ◽  
Activated T Cells ◽  
Inositol 1,4,5 Trisphosphate ◽  
Trisphosphate Receptor ◽  
Ca2 Channels

Sustained elevation of intracellular calcium by Ca2+ release–activated Ca2+ channels is required for lymphocyte activation. Sustained Ca2+ entry requires endoplasmic reticulum (ER) Ca2+ depletion and prolonged activation of inositol 1,4,5-trisphosphate receptor (IP3R)/Ca2+ release channels. However, a major isoform in lymphocyte ER, IP3R1, is inhibited by elevated levels of cytosolic Ca2+, and the mechanism that enables the prolonged activation of IP3R1 required for lymphocyte activation is unclear. We show that IP3R1 binds to the scaffolding protein linker of activated T cells and colocalizes with the T cell receptor during activation, resulting in persistent phosphorylation of IP3R1 at Tyr353. This phosphorylation increases the sensitivity of the channel to activation by IP3 and renders the channel less sensitive to Ca2+-induced inactivation. Expression of a mutant IP3R1-Y353F channel in lymphocytes causes defective Ca2+ signaling and decreased nuclear factor of activated T cells activation. Thus, tyrosine phosphorylation of IP3R1-Y353 may have an important function in maintaining elevated cytosolic Ca2+ levels during lymphocyte activation.

scholarly journals T-cell-receptor signalling in inositol 1,4,5-trisphosphate receptor (IP3R) type-1-deficient mice: is IP3R type 1 essential for T-cell-receptor signalling?

1998 ◽  
Vol 333 (3) ◽  
pp. 615-619 ◽  
Author(s):  
Junji HIROTA ◽  
Masashi BABA ◽  
Mineo MATSUMOTO ◽  
Teiichi FURUICHI ◽  
Kiyoshi TAKATSU ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Line ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Cell Phenotype ◽  
Receptor Signalling ◽  
Inositol 1,4,5 Trisphosphate ◽  
Trisphosphate Receptor

Stimulation of T-cells via the T-cell receptor (TCR) complex is accompanied by an increase in intracellular Ca2+ concentration ([Ca2+]i). Recently, it was reported that a stable transformant of the human T-cell line, Jurkat, expressing an antisense cDNA construct of inositol 1,4,5-trisphosphate receptor (IP3R) type 1 (IP3R1), failed to demonstrate increased [Ca2+]i or interleukin-2 production after TCR stimulation and was also resistant to apoptotic stimuli. This cell line lacked IP3R1 expression, but expressed the type-2 and -3 receptors, IP3R2 and IP3R3 respectively [Jayaraman, Ondriasova, Ondrias, Harnick and Marks (1995) Proc. Natl. Acad. Sci. U.S.A. 92, 6007–6011, and Jayaraman and Marks (1997) Mol. Cell. Biol. 17, 3005–3012]. The authors concluded that IP3R1 is essential for TCR signalling and suggested that Ca2+ release via IP3R1 is a critical mediator of apoptosis. To establish whether a loss of IP3R1 function in T-cells occurred in vivo and in vitro, we investigated Ca2+ signalling after TCR stimulation and the properties of T-cells using IP3R1-deficient (IP3R1-/-) mice. As IP3R1-/- mice die at weaning, we transplanted bone marrow cells of IP3R1-/- mice into irradiated wild-type mice. Western blot analysis showed that the recipient IP3R1-containing (IP3R1+/+) lymphocytes were replaced by the donor IP3R1-/- lymphocytes after transplantation and that expression of IP3R2 and IP3R3 was unaltered. In contrast with the previous reports, T-cells lacking IP3R1 were able to mobilize Ca2+ from intracellular Ca2+ stores after stimulation via the TCR. We observed no significant differences between IP3R1+/+ and IP3R1-/- T-cells in terms of the number of thymocytes and splenocytes, the proportion of the T-cell phenotype, proliferative response to anti-CD3 monoclonal antibody (mAb) stimulation and cell viability. Therefore IP3R1 is not essential for T-cell development and function.

A function for tyrosine phosphorylation of type 1 inositol 1,4,5-trisphosphate receptor in lymphocyte activation

2007 ◽  
Vol 204 (13) ◽  
pp. i30-i30
Author(s):  
Nikhil deSouza ◽  
Jie Cui ◽  
Miroslav Dura ◽  
Thomas V. McDonald ◽  
Andrew R. Marks
Keyword(s):  
Tyrosine Phosphorylation ◽  
Lymphocyte Activation ◽  
Inositol 1,4,5 Trisphosphate ◽  
Trisphosphate Receptor

scholarly journals Vγ4+ T Cells Promote Autoimmune CD8+ Cytolytic T-Lymphocyte Activation in Coxsackievirus B3-Induced Myocarditis in Mice: Role for CD4+ Th1 Cells

2002 ◽  
Vol 76 (21) ◽  
pp. 10785-10790 ◽  
Author(s):  
S. A. Huber ◽  
D. Sartini ◽  
M. Exley
Keyword(s):  
T Cells ◽  
Cell Activation ◽  
Cell Function ◽  
Adaptive Immune Response ◽  
Lymphocyte Activation ◽  
Cell Receptor ◽  
Coxsackievirus B3 ◽  
Th1 Cells ◽  
Ifn Γ

ABSTRACT T cells expressing the Vγ4 T-cell receptor (TCR) promote myocarditis in coxsackievirus B3 (CVB3)-infected BALB/c mice. CD1, a major histocompatibility complex (MHC) class I-like molecule, is required for activation of Vγ4+ cells. Once activated, Vγ4+ cells initiate myocarditis through gamma interferon (IFN-γ)-mediated induction of CD4+ T helper type 1 (Th1) cells in the infected animal. These CD4+ Th1 cells are required for activation of an autoimmune CD8+ αβ TCR+ effector, which is the predominant pathogenic agent in this model of CVB3-induced myocarditis. Activated Vγ4+ cells can adoptively transfer myocarditis into BALB/c mice infected with a nonmyocarditic variant of CVB3 (H310A1) but cannot transfer myocarditis into either uninfected or CD1−/− recipients, demonstrating the need for both infection and CD1 expression for Vγ4+ cell function. In contrast, CD8+ αβ TCR+ cells transfer myocarditis into either infected CD1−/− or uninfected recipients, showing that once activated, the CD8+ αβ TCR+ effectors function independently of both virus and CD1. Vγ4+ cells given to mice lacking CD4+ T cells minimally activate the CD8+ αβ TCR+ cells. These studies show that Vγ4+ cells determine CVB3 pathogenicity by their ability to influence both the CD4+ and CD8+ adaptive immune response. Vγ4+ cells enhance CD4+ Th1 (IFN-γ+) cell activation through IFN-γ- and CD1-dependent mechanisms. CD4+ Th1 cells promote activation of the autoimmune CD8+ αβ TCR+ effectors.

scholarly journals T cells deficient in inositol 1,4,5-trisphosphate receptor are resistant to apoptosis.

1997 ◽  
Vol 17 (6) ◽  
pp. 3005-3012 ◽  
Author(s):  
T Jayaraman ◽  
A R Marks
Keyword(s):  
T Cells ◽  
Intracellular Calcium ◽  
Calcium Release ◽  
Calcium Influx ◽  
Cell Receptor ◽  
Calcium Release Channel ◽  
Release Channel ◽  
Inositol 1,4,5 Trisphosphate ◽  
Intracellular Calcium Release ◽  
Trisphosphate Receptor

The type 1 inositol 1,4,5-trisphosphate receptor (IP3R1) calcium release channel is present on the endoplasmic reticulum of most cell types. T lymphocytes which have been made deficient in IP3R1 lack detectable IP3-induced intracellular calcium release and exhibit defective signaling via the T-cell receptor (TCR) (T. Jayaraman, E. Ondriasova, K. Ondrias, D. Harnick, and A. R. Marks, Proc. Natl. Acad. Sci. USA 92:6007-6011, 1995). We now show that IP3R1-deficient T cells are resistant to apoptosis induced by dexamethasone, TCR stimulation, ionizing radiation, and Fas. Resistance to TCR-mediated apoptosis in IP3R1-deficient cells is reversed by pharmacologically raising cytoplasmic calcium levels. TCR-mediated apoptosis can be induced in calcium-free media, indicating that extracellular calcium influx is not required. These findings suggest that intracellular calcium release via the IP3R1 is a critical mediator of apoptosis.

scholarly journals Activation of Nuclear Factor of Activated T Cells by Human T-Lymphotropic Virus Type 1 Accessory Protein p12I

2002 ◽  
Vol 76 (7) ◽  
pp. 3493-3501 ◽  
Author(s):  
Björn Albrecht ◽  
Celine D. D'Souza ◽  
Wei Ding ◽  
Susheela Tridandapani ◽  
K. Mark Coggeshall ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Persistent Infection ◽  
Lymphocyte Activation ◽  
Accessory Protein ◽  
Nuclear Factor ◽  
Activated T Cells ◽  
T Lymphotropic Virus ◽  
Calcium Dependent

ABSTRACT Human T-lymphotropic virus type 1 (HTLV-1) is the agent of an aggressive malignancy of CD4+ T lymphocytes, called adult T-cell lymphoma/leukemia, and is associated with numerous immune-mediated diseases. To establish infection, HTLV-1 must activate targeted T cells during early stages of infection. We recently demonstrated that the HTLV-1 accessory protein p12I is critical for persistent infection in vivo and for viral infectivity in quiescent primary lymphocytes, suggesting a role for p12I in lymphocyte activation. To test whether p12I modulates signaling pathways required for T-lymphocyte activation, we examined AP-1-, NF-κB-, and nuclear factor of activated T cells (NFAT)-driven reporter gene activity in p12I-expressing Jurkat T cells compared to vector-transfected control cells. HTLV-1 p12I specifically induced NFAT-mediated transcription approximately 20-fold in synergy with the Ras/mitogen-activated protein kinase pathway, but did not influence AP-1- or NF-κB-dependent gene expression. Inhibition of calcium-dependent signals by cyclosporin A, BAPTA-AM [glycine, N,N′-1,2-ethanediylbis(oxy-2,1-phenylene)-bis-N-2-(acetyloxy)methoxy-2-oxoethyl]-[bis(acetyloxy)methyl ester], and a dominant negative mutant of NFAT2 abolished the p12I-mediated activation of NFAT-dependent transcription. In contrast, inhibition of phospholipase C-γ and LAT (linker for activation of T cells) did not affect p12I-induced NFAT activity. Importantly, p12I functionally substituted for thapsigargin, which selectively depletes intracellular calcium stores. Our data are the first to demonstrate a role for HTLV-1 p12I in calcium-dependent activation of NFAT-mediated transcription in lymphoid cells. We propose a novel mechanism by which HTLV-1, a virus associated with lymphoproliferative disease, dysregulates common T-cell activation pathways critical for the virus to establish persistent infection.

scholarly journals Tespa1 regulates T cell receptor-induced calcium signals by recruiting inositol 1,4,5-trisphosphate receptors

2017 ◽  
Vol 8 (1) ◽  
Author(s):  
Jingjing Liang ◽  
Jun Lyu ◽  
Meng Zhao ◽  
Dan Li ◽  
Mingzhu Zheng ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
Calcium Signalling ◽  
Cell Receptor ◽  
Proximal Region ◽  
Thymocyte Development ◽  
Crucial Component ◽  
Inositol 1,4,5 Trisphosphate ◽  
Trisphosphate Receptor

Abstract Thymocyte-expressed, positive selection-associated 1 (Tespa1) is important in T cell receptor (TCR)-driven thymocyte development. Downstream of the TCR, Tespa1 is a crucial component of the linker for activation of T cells (LAT) signalosome, facilitating calcium signalling and subsequent MAPK activation. However, it is unknown how Tespa1 elicits calcium signalling. Here, we show that inositol 1,4,5-trisphosphate receptor type 1 (IP3R1) is crucial for Tespa1-optimized, TCR-induced Ca2+ flux and thymocyte development. Upon TCR stimulation, Tespa1 directly interacts with IP3R1 and recruits it to the TCR complex, where IP3R1 is phosphorylated at Y353 by Fyn. This Tespa1-IP3R1 interaction is mediated by the F187 and F188 residues of Tespa1 and the amino-terminus of IP3R1. Tespa1-F187A/F188A mutant mice phenocopy Tespa1-deficient mice with impaired late thymocyte development due to reduced IP3R1 translocation to the TCR-proximal region. Our work elucidates the function of Tespa1 in T cell development and the regulation of TCR-induced Ca2+ signalling through IP3R1.

scholarly journals Disrupted Ca2+ homeostasis and immunodeficiency in patients with functional Inositol 1,4,5-trisphosphate receptor subtype 3 defects

2021 ◽  
Author(s):  
Julika Neumann ◽  
Erika van Nieuwenhove ◽  
Lara E Terry ◽  
Frederik Staels ◽  
Taylor R Knebel ◽  
...  
Keyword(s):  
Lymphocyte Activation ◽  
Cell Receptor ◽  
Receptor Subtype ◽  
Compound Heterozygous ◽  
Inborn Errors ◽  
Hematopoietic Stem ◽  
Inositol 1,4,5 Trisphosphate ◽  
Severe Immunodeficiency ◽  
Compound Heterozygous Variants ◽  
Trisphosphate Receptor

Calcium signaling is essential for lymphocyte activation, with genetic disruptions resulting in severe immunodeficiency. The inositol 1,4,5-trisphosphate receptor (IP3R), formed from homo- or hetero-tetramers of the IP3R isoforms 1-3, amplifies lymphocyte signaling by releasing Ca2+ from ER stores into the cytosol following antigen-stimulation. While knockout of all 3 IP3R isoforms results in immunodeficiency in mice, the seeming redundancy of subunits was thought to explain the absence of IP3R mutation as a cause of human immunodeficiency. Here, we identify compound heterozygous variants in ITPR3 in two unrelated Caucasian patients presenting with combined immunodeficiency, in one case requiring hematopoietic stem cell transplantation. We observed disrupted Calcium homeostasis in patient-derived fibroblasts and immune cells, with abnormal proliferation and activation responses following B and T cell receptor stimulation. Reconstitution of IP3R knockout cell lines identified the variants as functional hypomorphs with reduced discrimination between homeostatic and induced states, validating a link between genotype and phenotype. These results demonstrate a functional linkage between defective ER Ca2+ channels and immunodeficiency, and identify IP3Rs as diagnostic targets for patients with specific inborn errors of immunity.

Differential modulation of inositol 1,4,5-trisphosphate receptor type 1 and type 3 by ATP

Cell Calcium ◽  
2000 ◽  
Vol 27 (5) ◽  
pp. 257-267 ◽  
Author(s):  
K. Maes ◽  
L. Missiaen ◽  
P. De Smet ◽  
S. Vanlingen ◽  
G. Callewaert ◽  
...  
Keyword(s):  
Receptor Type ◽  
Differential Modulation ◽  
Inositol 1,4,5 Trisphosphate ◽  
Trisphosphate Receptor ◽  
Type 3

T cells: a dedicated effector kinase pathways for every trait?

2021 ◽  
Vol 478 (6) ◽  
pp. 1303-1307
Author(s):  
Kriti Bahl ◽  
Jeroen P. Roose
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cell Receptor ◽  
Spectrometric Analysis ◽  
Activated T Cells ◽  
Biological Responses ◽  
Extracellular Signal ◽  
Differentiation And Proliferation

Signaling pathways play critical roles in regulating the activation of T cells. Recognition of foreign peptide presented by MHC to the T cell receptor (TCR) triggers a signaling cascade of proximal kinases and adapter molecules that lead to the activation of Effector kinase pathways. These effector kinase pathways play pivotal roles in T cell activation, differentiation, and proliferation. RNA sequencing-based methods have provided insights into the gene expression programs that support the above-mentioned cell biological responses. The proteome is often overlooked. A recent study by Damasio et al. [Biochem. J. (2021) 478, 79–98. doi:10.1042/BCJ20200661] focuses on characterizing the effect of extracellular signal-regulated kinase (ERK) on the remodeling of the proteome of activated CD8+ T cells using Mass spectrometric analysis. Surprisingly, the Effector kinase ERK pathway is responsible for only a select proportion of the proteome that restructures during T cell activation. The primary targets of ERK signaling are transcription factors, cytokines, and cytokine receptors. In this commentary, we discuss the recent findings by Damasio et al. [Biochem. J. (2021) 478, 79–98. doi:10.1042/BCJ20200661] in the context of different Effector kinase pathways in activated T cells.

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