scholarly journals BCL11B participates in the activation of IL2 gene expression in CD4+ T lymphocytes

Blood ◽  
2006 ◽  
Vol 108 (8) ◽  
pp. 2695-2702 ◽  
Author(s):  
Valeriu B. Cismasiu ◽  
Sailaja Ghanta ◽  
Javier Duque ◽  
Diana I. Albu ◽  
Hong-Mei Chen ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cells ◽  
T Cell ◽  
T Lymphocytes ◽  
T Cell Activation ◽  
Transcriptional Activation ◽  
Cd4 T Cells ◽  
Cell Activation ◽  
Critical Role ◽  
Interleukin 2

AbstractBCL11A and BCL11B are transcriptional regulators important for lymphopoiesis and previously associated with hematopoietic malignancies. Ablation of the mouse Bcl11b locus results in failure to generate double-positive thymocytes, implicating a critical role of Bcl11b in T-cell development. However, BCL11B is also expressed in CD4+ T lymphocytes, both in resting and activated states. Here we show both in transformed and primary CD4+ T cells that BCL11B participates in the control of the interleukin-2 (IL2) gene expression following activation through T-cell receptor (TCR). BCL11B augments expression from the IL2 promoter through direct binding to the US1 site. In addition, BCL11B associates with the p300 coactivator in CD4+ T cells activated through TCR, which may account for its transcriptional activation function. These results provide the first evidence that BCL11B, originally described as a transcriptional repressor, activates transcription of a target gene in the context of T-cell activation.

Signaling via LAT (linker for T-cell activation) and Syk/ZAP70 is required for ERK activation and NFAT transcriptional activation following CD2 stimulation

Blood ◽  
2000 ◽  
Vol 96 (6) ◽  
pp. 2181-2190 ◽  
Author(s):  
Maria Paola Martelli ◽  
Huamao Lin ◽  
Weiguo Zhang ◽  
Lawrence E. Samelson ◽  
Barbara E. Bierer
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Transcriptional Activation ◽  
Cell Activation ◽  
Interleukin 2 ◽  
Cell Receptor ◽  
Adapter Protein ◽  
Activated T Cells

Abstract Activation of T cells can be initiated through cell surface molecules in addition to the T-cell receptor-CD3 (TCR-CD3) complex. In human T cells, ligation of the CD2 molecule by mitogenic pairs of anti-CD2 monoclonal antibodies activates T cells via biochemical signaling pathways similar but not identical to those elicited on TCR engagement. This study describes a key role for the p36/38 membrane adapter protein linker for T cell activation (LAT) in CD2-mediated T-cell activation. Following ligation of CD2 on the surface of the Jurkat T-cell line and human purified T cells, LAT was tyrosine phosphorylated and shown to associate in vivo with a number of other tyrosine phosphorylated proteins including PLCγ-1, Grb-2, and SLP-76. Using Jurkat cell lines deficient in ZAP70/Syk (P116) or LAT (ANJ3) expression, CD2-dependent PLCγ-1 and SLP-76 tyrosine phosphorylation required expression both of ZAP70 or Syk and of LAT. As predicted, the absence of either LAT or ZAP70/Syk kinases correlated with a defect in the induction of nuclear factor of activated T cells (NFAT) transcriptional activity, activation of the interleukin-2 promoter, and ERK phosphorylation following CD2 stimulation. These data suggest that LAT is an adapter protein important for the regulation of CD2-mediated T-cell activation.

Signaling via LAT (linker for T-cell activation) and Syk/ZAP70 is required for ERK activation and NFAT transcriptional activation following CD2 stimulation

Blood ◽  
2000 ◽  
Vol 96 (6) ◽  
pp. 2181-2190 ◽  
Author(s):  
Maria Paola Martelli ◽  
Huamao Lin ◽  
Weiguo Zhang ◽  
Lawrence E. Samelson ◽  
Barbara E. Bierer
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Transcriptional Activation ◽  
Cell Activation ◽  
Interleukin 2 ◽  
Cell Receptor ◽  
Adapter Protein ◽  
Activated T Cells

Activation of T cells can be initiated through cell surface molecules in addition to the T-cell receptor-CD3 (TCR-CD3) complex. In human T cells, ligation of the CD2 molecule by mitogenic pairs of anti-CD2 monoclonal antibodies activates T cells via biochemical signaling pathways similar but not identical to those elicited on TCR engagement. This study describes a key role for the p36/38 membrane adapter protein linker for T cell activation (LAT) in CD2-mediated T-cell activation. Following ligation of CD2 on the surface of the Jurkat T-cell line and human purified T cells, LAT was tyrosine phosphorylated and shown to associate in vivo with a number of other tyrosine phosphorylated proteins including PLCγ-1, Grb-2, and SLP-76. Using Jurkat cell lines deficient in ZAP70/Syk (P116) or LAT (ANJ3) expression, CD2-dependent PLCγ-1 and SLP-76 tyrosine phosphorylation required expression both of ZAP70 or Syk and of LAT. As predicted, the absence of either LAT or ZAP70/Syk kinases correlated with a defect in the induction of nuclear factor of activated T cells (NFAT) transcriptional activity, activation of the interleukin-2 promoter, and ERK phosphorylation following CD2 stimulation. These data suggest that LAT is an adapter protein important for the regulation of CD2-mediated T-cell activation.

An emerging player in the adaptive immune response: microRNA-146a is a modulator of IL-2 expression and activation-induced cell death in T lymphocytes

Blood ◽  
2010 ◽  
Vol 115 (2) ◽  
pp. 265-273 ◽  
Author(s):  
Graziella Curtale ◽  
Franca Citarella ◽  
Claudia Carissimi ◽  
Marina Goldoni ◽  
Nicoletta Carucci ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Cell Death ◽  
T Cell ◽  
T Lymphocytes ◽  
T Cell Activation ◽  
Cell Activation ◽  
Interleukin 2 ◽  
Activation Induced Cell Death

Abstract Activation of the T cell–mediated immune response has been associated with changes in the expression of specific microRNAs (miRNAs). However, the role of miRNAs in the development of an effective immune response is just beginning to be explored. This study focuses on the functional role of miR-146a in T lymphocyte–mediated immune response and provides interesting clues on the transcriptional regulation of miR-146a during T-cell activation. We show that miR-146a is low in human naive T cells and is abundantly expressed in human memory T cells; consistently, miR-146a is induced in human primary T lymphocytes upon T-cell receptor (TCR) stimulation. Moreover, we identified NF-kB and c-ETS binding sites as required for the induction of miR-146a transcription upon TCR engagement. Our results demonstrate that several signaling pathways, other than inflammation, are influenced by miR-146a. In particular, we provide experimental evidence that miR-146a modulates activation-induced cell death (AICD), acting as an antiapoptotic factor, and that Fas-associated death domain (FADD) is a target of miR-146a. Furthermore, miR-146a enforced expression impairs both activator protein 1 (AP-1) activity and interleukin-2 (IL-2) production induced by TCR engagement, thus suggesting a role of this miRNA in the modulation of adaptive immunity.

Mechanism of Interleukin-10 Inhibition of T-Helper Cell Activation by Superantigen at the Level of the Cell Cycle

Blood ◽  
1999 ◽  
Vol 93 (1) ◽  
pp. 208-216 ◽  
Author(s):  
George Q. Perrin ◽  
Howard M. Johnson ◽  
Prem S. Subramaniam
Keyword(s):  
Cell Cycle ◽  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd4 T Cells ◽  
Cell Activation ◽  
Interleukin 2 ◽  
Interleukin 10 ◽  
Inhibitory Protein ◽  
Cell Functions

Abstract We have analyzed the effects of interleukin-10 (IL-10) on the entry of quiescent CD4+ T cells into the cell cycle upon stimulation with the superantigen staphylococcal enterotoxin B (SEB). IL-10 arrested cells at G0/G1. IL-10 treatment prevented the downregulation of p27Kip1, an inhibitory protein that controls progression out of the G0 phase of the cell cycle. IL-10 also prevented the upregulation of the G1 cyclins D2 and D3, proteins necessary for entry and progression through the G1 phase of the cell cycle. Associated with the inhibition of the cell cycle, IL-10 suppressed SEB induction of interleukin-2 (IL-2). Addition of exogenous IL-2 to IL-10–treated cells significantly reversed the antiproliferative effects of IL-10. Moreover, IL-10 effects on the early G1proteins p27Kip1 and cyclin D2 were similarly reversed by exogenous IL-2. Although this reversal by IL-2 was pronounced, it was not complete, suggesting that IL-10 may have some effects not directly related to the suppression of IL-2 production. Cell separation experiments suggest that IL-10 can effect purified CD4+ T cells directly, providing functional evidence for the presence of IL-10 receptors on CD4+ T cells. IL-10 also inhibited expression of IL-2 transcriptional regulators c-fos and c-jun, which also inhibit other cell functions. Our studies show that the mechanism of IL-10 regulation of quiescent CD4+ T-cell activation is mainly by blocking induction of IL-2 that is critical to downregulation of p27Kip1 and upregulation of D cyclins in T-cell activation and entry into the cell cycle.

Mechanism of Interleukin-10 Inhibition of T-Helper Cell Activation by Superantigen at the Level of the Cell Cycle

Blood ◽  
1999 ◽  
Vol 93 (1) ◽  
pp. 208-216
Author(s):  
George Q. Perrin ◽  
Howard M. Johnson ◽  
Prem S. Subramaniam
Keyword(s):  
Cell Cycle ◽  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd4 T Cells ◽  
Cell Activation ◽  
Interleukin 2 ◽  
Interleukin 10 ◽  
Inhibitory Protein ◽  
Cell Functions

We have analyzed the effects of interleukin-10 (IL-10) on the entry of quiescent CD4+ T cells into the cell cycle upon stimulation with the superantigen staphylococcal enterotoxin B (SEB). IL-10 arrested cells at G0/G1. IL-10 treatment prevented the downregulation of p27Kip1, an inhibitory protein that controls progression out of the G0 phase of the cell cycle. IL-10 also prevented the upregulation of the G1 cyclins D2 and D3, proteins necessary for entry and progression through the G1 phase of the cell cycle. Associated with the inhibition of the cell cycle, IL-10 suppressed SEB induction of interleukin-2 (IL-2). Addition of exogenous IL-2 to IL-10–treated cells significantly reversed the antiproliferative effects of IL-10. Moreover, IL-10 effects on the early G1proteins p27Kip1 and cyclin D2 were similarly reversed by exogenous IL-2. Although this reversal by IL-2 was pronounced, it was not complete, suggesting that IL-10 may have some effects not directly related to the suppression of IL-2 production. Cell separation experiments suggest that IL-10 can effect purified CD4+ T cells directly, providing functional evidence for the presence of IL-10 receptors on CD4+ T cells. IL-10 also inhibited expression of IL-2 transcriptional regulators c-fos and c-jun, which also inhibit other cell functions. Our studies show that the mechanism of IL-10 regulation of quiescent CD4+ T-cell activation is mainly by blocking induction of IL-2 that is critical to downregulation of p27Kip1 and upregulation of D cyclins in T-cell activation and entry into the cell cycle.

scholarly journals CD28-inducible transcription factor DEC1 is required for efficient autoreactive CD4+ T cell response

2013 ◽  
Vol 210 (8) ◽  
pp. 1603-1619 ◽  
Author(s):  
Marc Martínez-Llordella ◽  
Jonathan H. Esensten ◽  
Samantha L. Bailey-Bucktrout ◽  
Robert H. Lipsky ◽  
Ann Marini ◽  
...  
Keyword(s):  
T Cells ◽  
Transcription Factor ◽  
T Cell ◽  
T Cell Activation ◽  
Cd4 T Cells ◽  
Cell Activation ◽  
Critical Role ◽  
T Cell Response ◽  
Dependent Manner ◽  
Cell Functions

During the initial hours after activation, CD4+ T cells experience profound changes in gene expression. Co-stimulation via the CD28 receptor is required for efficient activation of naive T cells. However, the transcriptional consequences of CD28 co-stimulation are not completely understood. We performed expression microarray analysis to elucidate the effects of CD28 signals on the transcriptome of activated T cells. We show that the transcription factor DEC1 is highly induced in a CD28-dependent manner upon T cell activation, is involved in essential CD4+ effector T cell functions, and participates in the transcriptional regulation of several T cell activation pathways, including a large group of CD28-regulated genes. Antigen-specific, DEC1-deficient CD4+ T cells have cell-intrinsic defects in survival and proliferation. Furthermore, we found that DEC1 is required for the development of experimental autoimmune encephalomyelitis because of its critical role in the production of the proinflammatory cytokines GM-CSF, IFN-γ, and IL-2. Thus, we identify DEC1 as a critical transcriptional mediator in the activation of naive CD4+ T cells that is required for the development of a T cell–mediated autoimmune disease.

scholarly journals CD28 and T cell antigen receptor signal transduction coordinately regulate interleukin 2 gene expression in response to superantigen stimulation.

1992 ◽  
Vol 175 (4) ◽  
pp. 1131-1134 ◽  
Author(s):  
J D Fraser ◽  
M E Newton ◽  
A Weiss
Keyword(s):  
Gene Expression ◽  
Signal Transduction ◽  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Interleukin 2 ◽  
Signal Transduction Pathway ◽  
Transduction Pathway ◽  
Cell Antigen

Activation of an immune response requires intercellular contact between T lymphocytes and antigen-presenting cells (APC). Interaction of the T cell antigen receptor (TCR) with antigen in the context of major histocompatibility molecules mediates signal transduction, but T cell activation appears to require the induction of a second costimulatory signal transduction pathway. Recent studies suggest that interaction of CD28 with B7 on APC might deliver such a costimulatory signal. To investigate the role of CD28 signal transduction during APC-dependent T cell activation, we have used Staphylococcal enterotoxins (SEs) presented by a B7-positive APC. We used anti-B7 monoclonal antibodies and a mutant interleukin 2 (IL-2) promoter construct, unresponsive to CD28-generated signals, in transient transfection assays to examine the contribution of the CD28-B7 interaction to IL-2 gene activation. These studies indicate that the CD28-regulated signal transduction pathway is activated during SE stimulation of T cells and plays an important role in SE induction of IL-2 gene expression through its influence upon the CD28-responsive element contained within the IL-2 gene promoter. This effect is particularly profound in the activation of the IL-2 gene in peripheral blood T cells.

scholarly journals Phosphatidylinositol-3 Phosphatase Myotubularin-Related Protein 6 Negatively Regulates CD4 T Cells

2006 ◽  
Vol 26 (15) ◽  
pp. 5595-5602 ◽  
Author(s):  
Shekhar Srivastava ◽  
Kyung Ko ◽  
Papiya Choudhury ◽  
Zhai Li ◽  
Amanda K. Johnson ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd4 T Cells ◽  
Cell Activation ◽  
Critical Role ◽  
Cell Receptor ◽  
Negative Regulator ◽  
Related Protein ◽  
Phosphatidylinositol 3

ABSTRACT Intracellular Ca2+ levels rapidly rise following cross-linking of the T-cell receptor (TCR) and function as a critical intracellular second messenger in T-cell activation. It has been relatively under appreciated that K+ channels play an important role in Ca2+ influx into T lymphocytes by helping to maintain a negative membrane potential which provides an electrochemical gradient to drive Ca2+ influx. Here we show that the Ca2+-activated K+ channel, KCa3.1, which is critical for Ca2+ influx in reactivated naive T cells and central memory T cells, requires phosphatidylinositol-3 phosphatase [PI(3)P] for activation and is inhibited by the PI(3)P phosphatase myotubularin-related protein 6 (MTMR6). Moreover, by inhibiting KCa3.1, MTMR6 functions as a negative regulator of Ca2+ influx and proliferation of reactivated human CD4 T cells. These findings point to a new and unexpected role for PI(3)P and the PI(3)P phosphatase MTMR6 in the regulation of Ca2+ influx in activated CD4 T cells and suggest that MTMR6 plays a critical role in setting a minimum threshold for a stimulus to activate a T cell.

scholarly journals Arginine methylation regulates IL-2 gene expression: a role for protein arginine methyltransferase 5 (PRMT5)

2005 ◽  
Vol 388 (1) ◽  
pp. 379-386 ◽  
Author(s):  
Stéphane RICHARD ◽  
Mélanie MOREL ◽  
Patrick CLÉROUX
Keyword(s):  
Gene Expression ◽  
T Cells ◽  
T Cell ◽  
T Lymphocytes ◽  
T Cell Activation ◽  
Cell Activation ◽  
Arginine Methylation ◽  
Cytokine Gene Expression ◽  
Luciferase Reporter ◽  
Protein Arginine Methylation

Arginine methylation is a post-translational modification resulting in the generation of aDMAs (asymmetrical ω-NG, NG-dimethylated arginines) and sDMAs (symmetrical ω-NG, N′G-dimethylated arginines). The role of arginine methylation in cell signalling and gene expression in T lymphocytes is not understood. In the present study, we report a role for protein arginine methylation in regulating IL-2 (interleukin 2) gene expression in T lymphocytes. Leukaemic Jurkat T-cells treated with a known methylase inhibitor, 5′-methylthioadenosine, had decreased cytokine gene expression, as measured using an NF-AT (nuclear factor of activated T-cells)-responsive promoter linked to the luciferase reporter gene. Since methylase inhibitors block all methylation events, we performed RNA interference with small interfering RNAs against the major PRMT (protein arginine methyltransferases) that generates sDMA (PRMT5). The dose-dependent decrease in PRMT5 expression resulted in the inhibition of both IL-2- and NF-AT-driven promoter activities and IL-2 secretion. By using an sDMA-specific antibody, we observed that sDMA-containing proteins are directly associated with the IL-2 promoter after T-cell activation. Since changes in protein arginine methylation were not observed after T-cell activation in Jurkat and human peripheral blood lymphocytes, our results demonstrate that it is the recruitment of methylarginine-specific protein(s) to cytokine promoter regions that regulates their gene expression.

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