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.

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.

scholarly journals Immune function of the blood-brain barrier: incomplete presentation of protein (auto-)antigens by rat brain microvascular endothelium in vitro.

1990 ◽  
Vol 110 (5) ◽  
pp. 1757-1766 ◽  
Author(s):  
W Risau ◽  
B Engelhardt ◽  
H Wekerle
Keyword(s):  
T Cells ◽  
Endothelial Cells ◽  
T Cell ◽  
T Lymphocytes ◽  
Rat Brain ◽  
Blood Brain Barrier ◽  
T Cell Activation ◽  
Cell Activation ◽  
Ifn Gamma

The endothelial blood-brain barrier (BBB) has a critical role in controlling lymphocyte traffic into the central nervous system (CNS), both in physiological immunosurveillance, and in its pathological aberrations. The intercellular signals that possibly could induce lymphocytes to cross the BBB include immunogenic presentation of protein (auto-)antigens by BBB endothelia to circulating T lymphocytes. This concept has raised much, though controversial, attention. We approached this problem by analyzing in vitro immunospecific interactions between clonal rat T lymphocyte lines with syngeneic, stringently purified endothelial monolayer cultures from adult brain micro-vessels. The rat brain endothelia (RBE) were established from rat brain capillaries using double collagenase digestion, density gradient fractionation and selective cytolysis of contaminating pericytes by anti-Thy 1.1 antibodies and complement. Incubation with interferon-gamma in most of the brain-derived endothelial cells induced Ia-antigens in the cytoplasm and on the cell surface in some of the cells. Before the treatment, the cells were completely Ia-negative. Pericytes were unresponsive to IFN-gamma treatment. When confronted with syngeneic T cell lines specific for protein (auto-)antigens (e.g., ovalbumin and myelin basic protein, MBP), RBE were completely unable to induce antigen-specific proliferation of syngeneic T lymphocytes irrespective of pretreatment with IFN-gamma and of cell density. RBE were inert towards the T cells, and did not suppress T cell activation induced by other "professional" antigen presenting cells (APC) such as thymus-derived dendritic cells or macrophages. IFN-gamma-treated RBE were, however, susceptible to immunospecific T cell killing. They were lysed by MBP-specific T cells in the presence of the specific antigen or Con A. Antigen dependent lysis was restricted by the appropriate (MHC) class II product. We conclude that the interaction of brain endothelial cells with encephalitogenic T lymphocytes may involve recognition of antigen in the molecular context of relevant MHC products, but that this interaction per se is insufficient to initiate the full T cell activation program.

scholarly journals Nanoconfinement of Microvilli Alters Gene Expression and Boosts T cell Activation

2021 ◽  
Author(s):  
Morteza Aramesh ◽  
Diana Stoycheva ◽  
Ioana Sandu ◽  
Stephan J. Ihle ◽  
Tamara Zund ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cells ◽  
T Cell ◽  
Cell Signaling ◽  
T Cell Activation ◽  
Cell Activation ◽  
Local Environment ◽  
T Cell Signaling ◽  
Sense And Respond ◽  
Altered Gene

T cells sense and respond to their local environment at the nanoscale by forming small actin-rich protrusions, called microvilli, which play critical roles in signaling and antigen recognition, particularly at the interface with the antigen presenting cells. However, the mechanisms by which microvilli contribute to cell signaling and activation is largely unknown. Here, we present a tunable engineered system that promotes microvilli formation and T cell signaling via physical stimuli. We discovered that nanoporous surfaces favored microvilli formation, and markedly altered gene expression in T cells and promoted their activation. Mechanistically, confinement of microvilli inside of nanopores leads to size-dependent sorting of membrane-anchored proteins, specifically segregating CD45 phosphatases and T cell receptors (TCR) from the tip of the protrusions when microvilli are confined in 200 nm pores, but not in 400 nm pores. Consequently, formation of TCR nanoclustered hotspots within 200 nm pores, allows sustained and augmented signaling that prompts T cell activation even in the absence of TCR agonists. The synergistic combination of mechanical and biochemical signals on porous surfaces presents a straightforward strategy to investigate the role of microvilli in T cell signaling as well as to boost T cell activation and expansion for application in the growing field of adoptive immunotherapy.

Abstract P347: γδ T Cells Drive CD4 + And CD8 + T Cell Activation In Hypertension

Hypertension ◽  
2017 ◽  
Vol 70 (suppl_1) ◽  
Author(s):  
Antoine Caillon ◽  
Pierre Paradis ◽  
Ernesto L Schiffrin
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Lymphocytes ◽  
Vascular Injury ◽  
T Cell Activation ◽  
Cell Activation ◽  
Γδ T Cells ◽  
Ang Ii ◽  
Adaptive Immune Cells ◽  
Induced Hypertension

Objective: Both innate (monocyte/macrophages) and adaptive immune cells (T lymphocytes) have been shown to play a role in the development of vascular injury in hypertension. Recently, we demonstrated that a small subset of “innate-like” T lymphocytes, expressing the γ/δ T cell receptor (TCR) rather than the αβ TCR, plays a key role in hypertension and vascular injury. We demonstrated an increased number and activation (CD69 + ) of γδ T cells during the development of hypertension caused by angiotensin (Ang) II infusion, and that deficiency in γδ T cells prevented Ang II-induced hypertension, resistance artery endothelial dysfunction and spleen T-cell activation in mice. We hypothesized that γδ T cells mediate activation of other T cells in hypertension. Method and Results: Fourteen to 15-week old male C57BL/6 wild-type (WT) mice were infused with Ang II (490 ng/kg/min, SC) for 3, 7 and 14 days (n=5-7) and spleen T cell profile was determined by flow cytometry. A correlation was demonstrated between the frequency (FREQ) and the number (#) of activated CD69 + γδ T cells and CD4 + CD69 + T cells (FREQ: r=0.41, P <0.05 and #: r=0.58, P <0.001) and CD8 + CD69 + T cells (FREQ: r=0.36, P <0.05 and #: r=0.50, P <0.01). We also demonstrated a high correlation between the # of CD69 + γδ T cells expressing CD27, a marker of interferon-γ expressing cells and a member of the T-T interaction molecules, with CD4 + CD69 + (r=0.88, P <0.001) and CD8 + CD69 + (r=0.81, P <0.01) T cells after 7 days of Ang II infusion. Conclusion: This study demonstrated an association between CD27 + CD69 + γδ T cells and activated T cells. These results suggest that γδ T cells drive activation of other T cells in Ang II-induced hypertension. Targeting γδ T cells may contribute to reduce inflammation in hypertension.

Lysophosphatidic acid enhances interleukin-13 gene expression and promoter activity in T cells

2006 ◽  
Vol 290 (1) ◽  
pp. L66-L74 ◽  
Author(s):  
Joshua Rubenfeld ◽  
Jia Guo ◽  
Nitat Sookrung ◽  
Rongbing Chen ◽  
Wanpen Chaicumpa ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cells ◽  
T Cell ◽  
Signaling Pathways ◽  
T Cell Activation ◽  
Lysophosphatidic Acid ◽  
Cell Activation ◽  
Human Peripheral Blood ◽  
Regulatory Elements ◽  
Jurkat Cells

Lysophosphatidic acid (LPA) is a membrane-derived lysophospholipid with wide-ranging effects on multiple lung cells including airway epithelial and smooth muscle cells. LPA can augment migration and cytokine synthesis in lymphocytes, but its potential effects on Th2 cytokines have not been well studied. We examined the effects of physiological concentrations of LPA on IL-13 gene expression in human T cells. The Jurkat T cell line and human peripheral blood CD4+ T cells were incubated with LPA alone or with 1) pharmacological agonists of different signaling pathways, or 2) antibodies directed against the T cell receptor complex and costimulatory molecules. Luciferase-based reporter constructs driven by different lengths of the human IL-13 promoter were transfected by electroporation in Jurkat cells treated with and without LPA. The effects of LPA on IL-13 mRNA stability were examined using actinomycin D to halt ongoing transcription. Expression of mRNA encoding LPA2and LPP-1 increased with T cell activation. LPA augmented IL-13 secretion under conditions of submaximal T cell activation. This was observed using pharmacological agonists activating intracellular calcium-, PKC-, and cAMP-dependent signaling pathways, as well as antibodies directed against CD3 and CD28. LPA only slightly prolonged IL-13 mRNA half-life in submaximally stimulated Jurkat cells. In contrast, LPA significantly enhanced transcriptional activation of the IL-13 promoter via regulatory elements contained within proximal 312 bp. The effects of LPA on IL-13 promoter activation appeared to be distinct from those mediated by GATA-3. LPA can augment IL-13 gene expression in T cells, especially under conditions of submaximal activation.

scholarly journals Activation of virus replication after vaccination of HIV-1-infected individuals.

1995 ◽  
Vol 182 (6) ◽  
pp. 1727-1737 ◽  
Author(s):  
S I Staprans ◽  
B L Hamilton ◽  
S E Follansbee ◽  
T Elbeik ◽  
P Barbosa ◽  
...  
Keyword(s):  
T Cells ◽  
Steady State ◽  
T Cell ◽  
T Lymphocytes ◽  
T Cell Activation ◽  
Cell Activation ◽  
Vaccine Antigens ◽  
Steady State Levels ◽  
Hiv 1

Little is known about the factors that govern the level of HIV-1 replication in infected individuals. Recent studies (using potent antiviral drugs) of the kinetics of HIV-1 replication in vivo have demonstrated that steady-state levels of viremia are sustained by continuous rounds of de novo infection and the associated rapid turnover of CD4+ T lymphocytes. However, no information is available concerning the biologic variables that determine the size of the pool of T cells that are susceptible to virus infection or the amount of virus produced from infected cells. Furthermore, it is not known whether all CD4+ T lymphocytes are equally susceptible to HIV-1 infection at a given time or whether the infection is focused on cells of a particular state of activation or antigenic specificity. Although HIV-1 replication in culture is known to be greatly facilitated by T cell activation, the ability of specific antigenic stimulation to augment HIV-1 replication in vivo has not been studied. We sought to determine whether vaccination of HIV-1-infected adults leads to activation of virus replication and the targeting of vaccine antigen-responsive T cells for virus infection and destruction. Should T cell activation resulting from exposure to environmental antigens prove to be an important determinant of the steady-state levels of HIV-1 replication in vivo and lead to the preferential loss of specific populations of CD4+ T lymphocytes, it would have significant implications for our understanding of and therapeutic strategies for HIV-1 disease. To begin to address these issues, HIV-1-infected individuals and uninfected controls were studied by measurement of immune responses to influenza antigens and quantitation of virion-associated plasma HIV-1 RNA levels at baseline and at intervals after immunization with the trivalent influenza vaccine. Influenza vaccination resulted in readily demonstrable but transient increases in plasma HIV-1 RNA levels, indicative of activation of viral replication, in HIV-1-infected individuals with preserved ability to immunologically respond to vaccine antigens. Activation of HIV-1 replication by vaccination was more often seen and of greater magnitude in individuals who displayed a T cell proliferative response to vaccine antigens at baseline and in those who mounted a significant serologic response after vaccination. The fold increase in viremia, as well as the rates of increase of HIV-1 in plasma after vaccination and rates of viral decline after peak viremia, were higher in individuals with higher CD4+ T cell counts.(ABSTRACT TRUNCATED AT 400 WORDS)

scholarly journals Modulation of KV1.3 channels by protein kinase A I in T lymphocytes is mediated by the disc large 1-tyrosine kinase Lck complex

2012 ◽  
Vol 302 (10) ◽  
pp. C1504-C1512 ◽  
Author(s):  
Zerrin Kuras ◽  
Vladimir Kucher ◽  
Scott M. Gordon ◽  
Lisa Neumeier ◽  
Ameet A. Chimote ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Lymphocytes ◽  
Tyrosine Kinase ◽  
Signaling Pathway ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cell Function ◽  
Scaffolding Protein ◽  
T Cell Function

The cAMP/PKA signaling system constitutes an inhibitory pathway in T cells and, although its biochemistry has been thoroughly investigated, its possible effects on ion channels are still not fully understood. KV1.3 channels play an important role in T-cell activation, and their inhibition suppresses T-cell function. It has been reported that PKA modulates KV1.3 activity. Two PKA isoforms are expressed in human T cells: PKAI and PKAII. PKAI has been shown to inhibit T-cell activation via suppression of the tyrosine kinase Lck. The aim of this study was to determine the PKA isoform modulating KV1.3 and the signaling pathway underneath. 8-Bromoadenosine 3′,5′-cyclic monophosphate (8-BrcAMP), a nonselective activator of PKA, inhibited KV1.3 currents both in primary human T and in Jurkat cells. This inhibition was prevented by the PKA blocker PKI6–22. Selective knockdown of PKAI, but not PKAII, with siRNAs abolished the response to 8-BrcAMP. Additional studies were performed to determine the signaling pathway mediating PKAI effect on KV1.3. Overexpression of a constitutively active mutant of Lck reduced the response of KV1.3 to 8-Br-cAMP. Moreover, knockdown of the scaffolding protein disc large 1 (Dlg1), which binds KV1.3 to Lck, abolished PKA modulation of KV1.3 channels. Immunohistochemistry studies showed that PKAI, but not PKAII, colocalizes with KV1.3 and Dlg1 indicating a close proximity between these proteins. These results indicate that PKAI selectively regulates KV1.3 channels in human T lymphocytes. This effect is mediated by Lck and Dlg1. We thus propose that the KV1.3/Dlg1/Lck complex is part of the membrane pathway that cAMP utilizes to regulate T-cell function.

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.

scholarly journals T cell stimulation by staphylococcal enterotoxins. Clonally variable response and requirement for major histocompatibility complex class II molecules on accessory or target cells.

1988 ◽  
Vol 167 (5) ◽  
pp. 1697-1707 ◽  
Author(s):  
B Fleischer ◽  
H Schrezenmeier
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Lymphocytes ◽  
T Cell Activation ◽  
Cell Activation ◽  
Class Ii ◽  
T Cell Response ◽  
Target Cells ◽  
Beta Chain ◽  
Alpha Beta

Staphylococcal enterotoxins (SE) are the most potent mitogens for T lymphocytes known; concentrations of less than 10(-9) M are sufficient for T cell activation. The mechanism of T cell activation by SE is unknown. We have used cloned human cytotoxic and proliferative T lymphocytes to dissect the molecular mechanism of T cell activation by SE. With rare exceptions, all TCR alpha/beta chain-expressing T cell clones of CD4+ or CD8+ phenotype, as well as CD4-8- TCR alpha/beta chain negative chain-expressing T lymphocyte clones, respond with proliferation and/or cytotoxicity to SE. For triggering of all these clones, the presence of autologous or allogeneic MHC class II molecules on accessory or target cells is necessary. This requirement for class II antigens is not due to an immunological recognition of processed SE, since inhibition of antigen processing has no influence on the T cell response to SE. SE acts on the T cells directly since (a) they stimulate a rise in intracellular calcium concentration in T cell lines or purified T cells, and (b) accessory cells can be replaced by phorbolesters in the proliferative activation of resting T cells by SE. Furthermore, the T cell response to SE shows extensive clonal heterogeneity. These results suggest that SE are functionally bivalent mitogens binding highly selectively to HLA class II molecules and the TCR. Thus, compared with other polyclonal T cell activating agents, activation with SE most closely mimicks the physiological way of MHC-restricted antigen recognition by T lymphocytes.

Sign in / Sign up

Export Citation Format

Share Document