scholarly journals Regulation of 4F2 heavy-chain gene expression during normal human T-cell activation can be mediated by multiple distinct molecular mechanisms.

1988 ◽  
Vol 8 (9) ◽  
pp. 3820-3826 ◽  
Author(s):  
T Lindsten ◽  
C H June ◽  
C B Thompson ◽  
J M Leiden
Keyword(s):  
Gene Expression ◽  
T Cells ◽  
Steady State ◽  
T Cell Activation ◽  
Cell Activation ◽  
Molecular Mechanisms ◽  
Transcription Elongation ◽  
Fold Increase ◽  
Mrna Levels ◽  
Myristate Acetate

The 4F2 molecule belongs to the set of cell surface antigens which is induced following lectin- or antigen-mediated T-cell activation. The increase in 4F2 cell surface expression following lectin-mediated stimulation has been shown to be accompanied by a parallel increase in the steady-state levels of 4F2 heavy-chain (4F2HC) mRNA. The studies described in this report were designed to further elucidate the molecular mechanisms responsible for induction of 4F2HC gene expression following activation of normal resting human peripheral blood T cells. The low levels of mature 4F2HC mRNA in resting T cells were shown to be the result of a block to transcription elongation within the exon 1-intron 1 region of the 4F2HC gene rather than promoter inactivity. Phorbol myristate acetate stimulation of resting T cells resulted in a 20-fold increase in steady-state 4F2HC mRNA levels which was mediated by removal of this block to transcription elongation. The phorbol myristate acetate-induced increase in 4F2HC gene expression is distinct from previously described AP-1-mediated, phorbol ester-induced gene expression in that it requires new protein synthesis. Treatment of resting T cells with ionomycin plus PMA resulted in a 60-fold increase in 4F2HC mRNA levels. This induction was mediated by both an increase in promoter utilization and removal of the block to transcription elongation. Finally, by increasing the half-life of 4F2HC mRNA, cycloheximide treatment of resting T cells induced an approximately five fold increase in the levels of 4F2HC gene expression, although the physiologic significance of this mechanism remains unclear. These results demonstrate that the level of 4F2HC gene expression in normal peripheral blood T cells can be regulated by at least three distinct molecular pathways: (i) changes in promoter utilization, (ii) modulation of a block to transcription elongation, and (iii) alteration in mRNA stability.

Regulation of 4F2 heavy-chain gene expression during normal human T-cell activation can be mediated by multiple distinct molecular mechanisms

1988 ◽  
Vol 8 (9) ◽  
pp. 3820-3826
Author(s):  
T Lindsten ◽  
C H June ◽  
C B Thompson ◽  
J M Leiden
Keyword(s):  
Gene Expression ◽  
T Cells ◽  
Steady State ◽  
T Cell Activation ◽  
Cell Activation ◽  
Molecular Mechanisms ◽  
Transcription Elongation ◽  
Fold Increase ◽  
Mrna Levels ◽  
Myristate Acetate

The 4F2 molecule belongs to the set of cell surface antigens which is induced following lectin- or antigen-mediated T-cell activation. The increase in 4F2 cell surface expression following lectin-mediated stimulation has been shown to be accompanied by a parallel increase in the steady-state levels of 4F2 heavy-chain (4F2HC) mRNA. The studies described in this report were designed to further elucidate the molecular mechanisms responsible for induction of 4F2HC gene expression following activation of normal resting human peripheral blood T cells. The low levels of mature 4F2HC mRNA in resting T cells were shown to be the result of a block to transcription elongation within the exon 1-intron 1 region of the 4F2HC gene rather than promoter inactivity. Phorbol myristate acetate stimulation of resting T cells resulted in a 20-fold increase in steady-state 4F2HC mRNA levels which was mediated by removal of this block to transcription elongation. The phorbol myristate acetate-induced increase in 4F2HC gene expression is distinct from previously described AP-1-mediated, phorbol ester-induced gene expression in that it requires new protein synthesis. Treatment of resting T cells with ionomycin plus PMA resulted in a 60-fold increase in 4F2HC mRNA levels. This induction was mediated by both an increase in promoter utilization and removal of the block to transcription elongation. Finally, by increasing the half-life of 4F2HC mRNA, cycloheximide treatment of resting T cells induced an approximately five fold increase in the levels of 4F2HC gene expression, although the physiologic significance of this mechanism remains unclear. These results demonstrate that the level of 4F2HC gene expression in normal peripheral blood T cells can be regulated by at least three distinct molecular pathways: (i) changes in promoter utilization, (ii) modulation of a block to transcription elongation, and (iii) alteration in mRNA stability.

scholarly journals Immunomodulatory Effects of Polysaccharide from Marine FungusPhoma herbarumYS4108 on T Cells and Dendritic Cells

2014 ◽  
Vol 2014 ◽  
pp. 1-13 ◽  
Author(s):  
Song Chen ◽  
Ran Ding ◽  
Yan Zhou ◽  
Xian Zhang ◽  
Rui Zhu ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Molecular Mechanisms ◽  
Interleukin 12 ◽  
Related Factors ◽  
Knock Out ◽  
Specific Immunity

YCP, as a kind of natural polysaccharides from the mycelium of marine filamentous fungusPhoma herbarumYS4108, has great antitumor potentialviaenhancement of host immune response, but little is known about the molecular mechanisms. In the present study, we mainly focused on the effects and mechanisms of YCP on the specific immunity mediated by dendritic cells (DCs) and T cells. T cell /DC activation-related factors including interferon- (IFN-)γ, interleukin-12 (IL-12), and IL-4 were examined with ELISA. Receptor knock-out mice and fluorescence-activated cell sorting are used to analyze the YCP-binding receptor of T cells and DCs. RT-PCR is utilized to measure MAGE-A3 for analyzing the tumor-specific killing effect. In our study, we demonstrated YCP can provide the second signal for T cell activation, proliferation, and IFN-γproduction through binding to toll-like receptor- (TLR-) 2 and TLR-4. YCP could effectively promote IL-12 secretion and expression of markers (CD80, CD86, and MHC II)viaTLR-4 on DCs. Antigen-specific immunity against mouse melanoma cells was strengthened through the activation of T cells and the enhancement of capacity of DCs by YCP. The data supported that YCP can exhibit specific immunomodulatory capacity mediated by T cells and DCs.

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.

A calcineurin- and NFAT-dependent pathway regulates Myf5 gene expression in skeletal muscle reserve cells

2001 ◽  
Vol 114 (2) ◽  
pp. 303-310 ◽  
Author(s):  
B.B. Friday ◽  
G.K. Pavlath
Keyword(s):  
Gene Expression ◽  
Skeletal Muscle ◽  
Satellite Cell ◽  
Cell Activation ◽  
Molecular Mechanisms ◽  
Fiber Type ◽  
Calcium Ionophore ◽  
Cell Populations ◽  
Mrna Levels ◽  
Dependent Pathway

Myf5 is a member of the muscle regulatory factor family of transcription factors and plays an important role in the determination, development, and differentiation of skeletal muscle. However, factors that regulate the expression and activity of Myf5 itself are not well understood. Recently, a role for the calcium-dependent phosphatase calcineurin was suggested in three distinct pathways in skeletal muscle: differentiation, hypertrophy, and fiber-type determination. We propose that one downstream target of calcineurin and the calcineurin substrate NFAT in skeletal muscle is regulation of Myf5 gene expression. For these studies, we used myotube cultures that contain both multinucleated myotubes and quiescent, mononucleated cells termed ‘reserve’ cells, which share many characteristics with satellite cells. Treatment of such myotube cultures with the calcium ionophore ionomycin results in an approximately 4-fold increase in Myf5 mRNA levels, but similar effects are not observed in proliferating myoblast cultures indicating that Myf5 is regulated by different pathways in different cell populations. The increase in Myf5 mRNA levels in myotube cultures requires the activity of calcineurin and NFAT, and can be specifically enhanced by overexpressing the NFATc isoform. We used immunohistochemical analyses and fractionation of the cell populations to demonstrate that the calcium regulated expression of Myf5 occurs in the mononucleated reserve cells. We conclude that Myf5 gene expression is regulated by a calcineurin- and NFAT-dependent pathway in the reserve cell population of myotube cultures. These results may provide important insights into the molecular mechanisms responsible for satellite cell activation and/or the renewal of the satellite cell pool following activation and proliferation.

scholarly journals Human T cell activation. IV. T cell activation and proliferation via the early activation antigen EA 1.

1989 ◽  
Vol 169 (3) ◽  
pp. 677-689 ◽  
Author(s):  
S Nakamura ◽  
S S Sung ◽  
J M Bjorndahl ◽  
S M Fu
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Early Activation ◽  
Human T Cell ◽  
Accessory Cells ◽  
Activation Antigen

A new mAb G38 was generated against purified EA 1, an early activation antigen. In immunoprecipitation, it was reactive with the same complex precipitated by the initial anti-EA 1 mAb P8. mAb G38 augmented PMA-induced proliferation of PBMC. It was shown to be mitogenic for purified T cells in collaboration with PMA in a dose-dependent manner. This effect was independent of monocytes and other accessory cells. mAb G38 augmented PMA-induced IL-2-R expression. In conjunction with PMA, it induced IL-2 synthesis and secretion. Its effects on IL-2-R and IL-2 expression were documented at both protein and mRNA levels. Both anti-EA 1 mAbs did not induce Ca2+ influx by themselves in PMA-treated T cells. However, the addition of second anti-mouse Ig antibodies induced readily detectable increases in [Ca2+]i. Ca2+-mediated pathways may be utilized as the transduction signal mechanisms. mAb Leu-23 was shown to be reactive with EA 1. mAb Leu-23 was also mitogenic for T cells in the presence of PMA. These findings provide evidence for a functional role for EA 1 in T cell activation and proliferation.

scholarly journals Induction of c-ets and c-fos gene expression upon antigenic stimulation of a T cell hybridoma with inducible cytolytic capacity.

1987 ◽  
Vol 166 (3) ◽  
pp. 810-815 ◽  
Author(s):  
Y Kaufmann ◽  
T Silverman ◽  
B Z Levi ◽  
K Ozato
Keyword(s):  
Gene Expression ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Specific Antigen ◽  
Functional Differentiation ◽  
Mrna Levels ◽  
Cellular Oncogenes ◽  
Differentiation Of Lymphocytes ◽  
Stimulation Of

Expression of cellular oncogenes was studied in a T cell hybridoma that undergoes cytolytic activation when stimulated by specific antigen or by anti-Thy-1 antibody. The activation occurs without induction of hybridoma proliferation, providing a model to examine oncogene expression during functional differentiation of lymphocytes. We found that c-fos and c-ets-1 mRNAs were transiently induced at high levels in the hybridoma 30 min and 4 h after stimulation, respectively. c-myc and c-ets-2 oncogenes were constitutively expressed in the hybridoma and their mRNA levels were unaffected during 4 h of stimulation, although c-myc expression was reduced in the later stage of stimulation. Inhibitors of T cell activation, cyclosporin A and anti-LFA-1 antibody, blocked the induction of c-fos and c-ets-1 mRNAs without reducing the levels of c-myc and c-ets-2. The results indicate that the functional activation of the CTL hybridoma is associated with induction of c-fos and c-ets-1 genes.

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.

Molecular Transfer of Human CD40 and OX40 Ligands to Leukemic Human B-CLL Cells Extensively Expands Tumor-Reactive Cytotoxic T-Lymphocytes.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 951-951
Author(s):  
Ettore Biagi ◽  
Giampietro Dotti ◽  
Eric Yvon ◽  
Raphael Rousseau ◽  
Edward Lee ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Cell Activation ◽  
Fold Increase ◽  
Mean Value ◽  
Lymphocytic Leukemia ◽  
Molecular Transfer

Abstract CD40 ligand is an accessory signal for T-cell activation and can overcome T-cell anergy. The OX40-OX40 ligand pathway is involved in the subsequent expansion of memory T cells. We expressed both human CD40L and OX40L on B-Chronic Lymphocytic Leukemia (B-CLL) cells, by exploiting the phenomenon of molecular transfer from fibroblasts engineered to over-express both of these TNF-receptor superfamily members. We analyzed the effects of the modified B-CLL cells on the number, phenotype and cytotoxic function of autologous T cells in seven B-CLL patients. Transfer of CD40L and OX40L to B-CLL cells was observed in all patients (mean value from 1% pre to 76% post for CD40L; from 0.7% pre to 88% post for OX40L). Subsequent up-regulation of the costimulatory molecules CD80 (B7-1) and CD86 (B7-2) was obtained after engagement of the endogenous CD40 receptor on B-CLL by the transferred CD40L molecules (mean value from 8% pre to 64% post for CD80; from 36% pre to 95% post for CD86). Co-culture of modified and unmodified B-CLL cells with autologous T cells revealed profound differences in the immune responses they induced. With unmodified B-CLL cells, or cells expressing either CD40L or OX40L individually, less than a 10-fold expansion of autologous T cells was observed, with a <100-fold expansion in tumor reactive T cells (measured by IFN-gamma Elispot with autologous B-CLL cells as stimulators, and allogeneic B-CLL cells as controls). By contrast, co-culture with B-CLL cells expressing both CD40L and OX40L induced a >40 fold expansion of autologous T cells - including both CD8+ T cells and CD4+ T cells with a Th1 pattern of cytokine release - and a >2500-fold increase in leukemia-reactive T cells. These expanded T cells were also directly cytotoxic to B-CLL targets, producing a mean 48% B-CLL killing at an E:T ratio of 10:1. A proportion of these tumor-reactive CD8+ T cells were specific for survivin, a B-CLL associated tumor antigen. Hence the combination of CD40L and OX40L expression by B-CLL cells allows generation of potent immune responses to B-CLL, which may be exploitable either by using active immunization with CD40L/OX40L-modified tumor cells or by adoptive immunotherapy with CD40L/OX40L generated tumor-reactive T cells.

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 iPABP, an inducible poly(A)-binding protein detected in activated human T cells.

1995 ◽  
Vol 15 (12) ◽  
pp. 6770-6776 ◽  
Author(s):  
H Yang ◽  
C S Duckett ◽  
T Lindsten
Keyword(s):  
T Cells ◽  
T Cell Activation ◽  
Cell Activation ◽  
Rna Binding ◽  
Binding Protein ◽  
Amino Acid Level ◽  
Binding Activity ◽  
Mrna Levels ◽  
Activated T Cells ◽  
Human T Cells

The poly(A)-binding protein (PABP) binds to the poly(A) tail present at the 3' ends of most eukaryotic mRNAs. PABP is thought to play a role in both translation and mRNA stability. Here we describe the molecular cloning and characterization of an inducible PABP, iPABP, from a cDNA library prepared from activated T cells. iPABP shows 79% sequence identity to PABP at the amino acid level. The RNA binding domains of iPABP and PABP are nearly identical, while their C termini are more divergent. Like PABP, iPABP is primarily localized to the cytoplasm. iPABP is expressed at low levels in resting normal human T cells; following T-cell activation, however, iPABP mRNA levels are rapidly up-regulated. In contrast, PABP is constitutively expressed in both resting and activated T cells. iPABP mRNA was also expressed at much higher levels than PABP mRNA in heart and skeletal muscle tissue. These data suggest that the regulation of cytoplasmic poly(A)-binding activity is more complex than previously believed. In most tissues, poly(A)-binding activity is likely to be the result of the combined effects of constitutively expressed PABP and iPABP, whose expression is subject to more complex regulation.

Sign in / Sign up

Export Citation Format

Share Document