scholarly journals Regulation of the interleukin-2 CD28-responsive element by NF-ATp and various NF-kappaB/Rel transcription factors.

1997 ◽  
Vol 17 (5) ◽  
pp. 2605-2614 ◽  
Author(s):  
S B Maggirwar ◽  
E W Harhaj ◽  
S C Sun
Keyword(s):  
T Cells ◽  
Transcription Factors ◽  
Gene Transcription ◽  
Binding Proteins ◽  
Interleukin 2 ◽  
Activated T Cells ◽  
Costimulatory Signal ◽  
Enhancer Binding Proteins ◽  
Nf Kappab ◽  
Responsive Element

The CD28 costimulatory signal enhances antigen-mediated induction of interleukin-2 (IL-2) gene transcription through activation of an enhancer termed the CD28-responsive element (CD28RE). Although various nuclear proteins have been shown to bind to CD28RE, their in vivo functions in the regulation of this enhancer remain elusive. In this report, we show that CD28RE binds distinct transcription factors in cells treated with different mitogenic stimuli. Stimulation of the T-cell receptor (TCR) complex in the absence of a CD28 costimulatory signal induces a member of the nuclear factor of the activated T cells, NF-ATp; however, this treatment fails to activate the CD28RE enhancer activity. Significant activation of CD28RE was detected when the cells were treated with both the TCR stimulators and an anti-CD28 monoclonal antibody (anti-CD28), which induces the NF-kappaB/Rel enhancer binding proteins in addition to NF-ATp. The costimulatory activity of anti-CD28 can be further enhanced by a phorbol ester. Kinetic analyses demonstrate that activation of endogenous IL-2 gene transcription is correlated with the binding of CD28RE by NF-ATp and different NF-kappaB/Rel species. Transient-transfection studies reveal that expression of either NF-ATp or the p50-RelA NF-kappaB heterodimer leads to the potent transactivation of both the CD28RE enhancer and the intact IL-2 promoter in mitogen-stimulated cells. Remarkably, coexpression of these two families of enhancer-binding proteins in Jurkat T cells results in the transactivation of the CD28RE enhancer even in the absence of any cellular stimuli. Together, these results suggest that activation of IL-2 gene transcription by the TCR- and CD28-mediated signals involves the interaction of CD28RE with NF-ATp and various NF-kappaB/Rel transcription factors.

scholarly journals CD28 mediates a potent costimulatory signal for rapid degradation of IkappaBbeta which is associated with accelerated activation of various NF-kappaB/Rel heterodimers.

1996 ◽  
Vol 16 (12) ◽  
pp. 6736-6743 ◽  
Author(s):  
E W Harhaj ◽  
S B Maggirwar ◽  
L Good ◽  
S C Sun
Keyword(s):  
Late Phase ◽  
Interleukin 2 ◽  
Underlying Mechanism ◽  
Cell Receptor ◽  
Rapid Degradation ◽  
Costimulatory Signal ◽  
Cd28 Costimulation ◽  
Truncation Mutant ◽  
Nf Kappab ◽  
Responsive Element

Optimal activation of T cells requires at least two signals delivered by the T-cell receptor complex and costimulatory molecules such as CD28. The CD28 signaling participates in the transcription of the interleukin-2 gene through activation of an enhancer termed the CD28-responsive element (CD28RE). Stimulation of CD28 enhances mitogen-mediated induction of CD28RE-binding proteins including members of the NF-kappaB/Rel transcription factor family, although the underlying mechanism remains elusive. In this report, we show that CD28 costimulation leads to biphasic induction of NF-kappaB/Rel heterodimers, including early-phase induction of p50/RelA and c-Rel/RelA and late-phase induction of p50/c-Rel. Interestingly, activation of these NF-kappaB/Rel complexes by the CD28 signal is associated with the rapid degradation of both IkappaBalpha and IkappaBbeta, two major cytoplasmic inhibitors of NF-kappaB/Rel. Although IkappaBalpha degradation can be induced by phorbol ester alone, degradation of IkappaBbeta is largely dependent on the CD28 costimulatory signal. We further demonstrate that CD28-mediated transactivation of the CD28RE enhancer is potently inhibited by an N-terminal truncation mutant of IkappaBbeta that is incapable of responding to the degradation signals. Together, these results suggest that the CD28 costimulatory signal augments activation of NF-kappaB/Rel by promoting degradation of IkappaBbeta as well as enhancing degradation of IkappaBalpha and that induction of NF-kappaB/Rel serves as an essential step in the signal-mediated activation of the CD28RE enhancer.

scholarly journals Constitutive NF-κB and NFAT activation in aggressive B-cell lymphomas synergistically activates the CD154 gene and maintains lymphoma cell survival

Blood ◽  
2005 ◽  
Vol 106 (12) ◽  
pp. 3940-3947 ◽  
Author(s):  
Lan V. Pham ◽  
Archito T. Tamayo ◽  
Linda C. Yoshimura ◽  
Yen-Chiu Lin-Lee ◽  
Richard J. Ford
Keyword(s):  
T Cells ◽  
Transcription Factors ◽  
B Cell ◽  
Gene Transcription ◽  
B Lymphocyte ◽  
B Cell Lymphoma ◽  
Lymphoma Cell ◽  
Nuclear Factor ◽  
B Cell Lymphomas ◽  
Activated T Cells

Abnormalities in B-lymphocyte CD40 ligand (CD154) expression have been described for a number of immunologic diseases, including B-cell lymphomas. Although functional analysis of the CD154 gene and protein has been extensive, little is known about the mechanisms controlling CD154 expression in activated T cells, and even less is known for normal and malignant B cells. In this study we describe the transcriptional mechanism controlling CD154 expression in large B-cell lymphoma (LBCL). We show that the nuclear factor of activated T cells (NFAT) transcription factor is also constitutively activated in LBCL. We demonstrate that the constitutively active NFATc1 and c-rel members of the NFAT and nuclear factor–κB (NF-κB) families of transcription factors, respectively, directly interact with each other, bind to the CD154 promoter, and synergistically activate CD154 gene transcription. Down-regulation of NFATc1 or c-rel with small interfering RNA (siRNA) or chemical inhibitors inhibits CD154 gene transcription and lymphoma cell growth. These findings suggest that targeting NF-κB and NFAT, by inhibiting the expression of these transcription factors, or interdicting their interaction may provide a therapeutic rationale for patients with non-Hodgkin lymphoma of B-cell origin, and possibly other disorders that display dysregulated CD154 expression.

scholarly journals Nuclear factor of activated T cells is associated with a mast cell interleukin 4 transcription complex.

1996 ◽  
Vol 16 (1) ◽  
pp. 228-235 ◽  
Author(s):  
D L Weiss ◽  
J Hural ◽  
D Tara ◽  
L A Timmerman ◽  
G Henkel ◽  
...  
Keyword(s):  
T Cells ◽  
Mast Cell ◽  
T Cell ◽  
Mast Cells ◽  
Gene Transcription ◽  
Family Members ◽  
Interleukin 4 ◽  
Nuclear Factor ◽  
Activated T Cells ◽  
Responsive Element

Interleukin 4 (IL-4), an immunoregulatory cytokine, is produced only by a subset of activated T cells and cells of the mast cell-basophil lineage. The production of IL-4 by mast cells likely represents a significant source of this protein in local immune-inflammatory responses in the skin, brain, gastrointestinal, and respiratory tracts, in which mast cells are prevalent. In the present study, the cis- and trans-acting elements that control inducible mast cell IL-4 gene transcription were examined and compared with those that function in T cells. We demonstrate that, as in T cells, sequences between bp -87 and -70 are critical for protein association and activation-dependent gene transcription and that this region (termed the activation-responsive element region) is the target of an inducible, cyclosporin A-sensitive, DNA-protein interaction. When assessed by electrophoretic mobility shift assays and UV cross-linking analyses, multiple proteins in both T- and mast cell nuclear extracts associate with the activation-responsive element in vitro, and some of these appear identical. However, distinct proteins are associated with each of the complexes as well. AP-1 family members are unique to the T-cell-stimulation-dependent complex, whereas mast cell complexes contain factors that are reactive with anti-nuclear factor of activated T cells p (NF-ATp) and anti-NF-ATc antibodies but have distinct molecular masses compared with those of T-cell-derived NF-AT. Furthermore, an anti-NF-ATp-reactive factor with a molecular mass of approximately 41 kDa is present in the nuclei of unstimulated cells and binds independently of cell activation, unlike the previously described NF-AT family members. These data support the idea that there are uniquely regulated, cell lineage-specific transcription factors related to T-cell-derived NF-AT that mediate inducible IL-4 transcription in mast cells. These differences likely reflect the distinct cell surface signaling requirements for IL-4 production in T and mast cells.

scholarly journals Blockade of T-cell activation by dithiocarbamates involves novel mechanisms of inhibition of nuclear factor of activated T cells.

1997 ◽  
Vol 17 (11) ◽  
pp. 6437-6447 ◽  
Author(s):  
S Martínez-Martínez ◽  
P Gómez del Arco ◽  
A L Armesilla ◽  
J Aramburu ◽  
C Luo ◽  
...  
Keyword(s):  
T Cells ◽  
Transcription Factor ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Regulation Of Gene Expression ◽  
Interleukin 2 ◽  
Nuclear Factor ◽  
Activated T Cells ◽  
Nf Kappab

Dithiocarbamates (DTCs) have recently been reported as powerful inhibitors of NF-kappaB activation in a number of cell types. Given the role of this transcription factor in the regulation of gene expression in the inflammatory response, NF-kappaB inhibitors have been suggested as potential therapeutic drugs for inflammatory diseases. We show here that DTCs inhibited both interleukin 2 (IL-2) synthesis and membrane expression of antigens which are induced during T-cell activation. This inhibition, which occurred with a parallel activation of c-Jun transactivating functions and expression, was reflected by transfection experiments at the IL-2 promoter level, and involved not only the inhibition of NF-kappaB-driven reporter activation but also that of nuclear factor of activated T cells (NFAT). Accordingly, electrophoretic mobility shift assays (EMSAs) indicated that pyrrolidine DTC (PDTC) prevented NF-kappaB, and NFAT DNA-binding activity in T cells stimulated with either phorbol myristate acetate plus ionophore or antibodies against the CD3-T-cell receptor complex and simultaneously activated the binding of AP-1. Furthermore, PDTC differentially targeted both NFATp and NFATc family members, inhibiting the transactivation functions of NFATp and mRNA induction of NFATc. Strikingly, Western blotting and immunocytochemical experiments indicated that PDTC promoted a transient and rapid shuttling of NFATp and NFATc, leading to their accelerated export from the nucleus of activated T cells. We propose that the activation of an NFAT kinase by PDTC could be responsible for the rapid shuttling of the NFAT, therefore transiently converting the sustained transactivation of this transcription factor that occurs during lymphocyte activation, and show that c-Jun NH2-terminal kinase (JNK) can act by directly phosphorylating NFATp. In addition, the combined inhibitory effects on NFAT and NF-KB support a potential use of DTCs as immunosuppressants.

scholarly journals Integration of Calcium and Cyclic AMP Signaling Pathways by 14-3-3

2000 ◽  
Vol 20 (2) ◽  
pp. 702-712 ◽  
Author(s):  
Chi-Wing Chow ◽  
Roger J. Davis
Keyword(s):  
T Cells ◽  
Cyclic Amp ◽  
Signaling Pathways ◽  
Interleukin 2 ◽  
Camp Signaling ◽  
Phosphorylation Sites ◽  
Nuclear Factor ◽  
Activated T Cells ◽  
Transcription Activity ◽  
Kinase A

ABSTRACT Calcium-stimulated nuclear factor of activated T cells (NFAT) transcription activity at the interleukin-2 promoter is negatively regulated by cyclic AMP (cAMP). This effect of cAMP is mediated, in part, by protein kinase A phosphorylation of NFAT. The mechanism of regulation involves the creation of a phosphorylation-dependent binding site for 14-3-3. Decreased NFAT phosphorylation caused by the calcium-stimulated phosphatase calcineurin, or mutation of the PKA phosphorylation sites, disrupted 14-3-3 binding and increased NFAT transcription activity. In contrast, NFAT phosphorylation caused by cAMP increased 14-3-3 binding and reduced NFAT transcription activity. The regulated interaction between NFAT and 14-3-3 provides a mechanism for the integration of calcium and cAMP signaling pathways.

Down-regulation of Fas-Associated Phosphatase-1 (FAP-1) in Interleukin-2-Activated T Cells

1998 ◽  
Vol 186 (2) ◽  
pp. 103-110 ◽  
Author(s):  
Yan-Wen Zhou ◽  
Yoshihiro Komada ◽  
Hiroto Inaba ◽  
Eiichi Azuma ◽  
Minoru Sakurai
Keyword(s):  
T Cells ◽  
Interleukin 2 ◽  
Down Regulation ◽  
Activated T Cells

scholarly journals Human Articular Chondrocytes Induce Interleukin-2 Nonresponsiveness to Allogeneic Lymphocytes

Cartilage ◽  
2016 ◽  
Vol 8 (3) ◽  
pp. 300-306 ◽  
Author(s):  
Satomi Abe ◽  
Hitoshi Nochi ◽  
Hiroshi Ito
Keyword(s):  
T Cells ◽  
Articular Chondrocytes ◽  
Interleukin 2 ◽  
Flow Cytometric Analysis ◽  
Third Party ◽  
Soluble Form ◽  
Enzyme Linked Immunosorbent Assay ◽  
Dependent Manner ◽  
Activated T Cells ◽  
Allogeneic Lymphocytes

Introduction We previously showed that articular chondrocytes (ACs) have immune privilege and immunomodulatory functions like those of mesenchymal stem cells. To elucidate these mechanisms, we focused on interleukin-2 (IL-2), which plays critical roles in lymphocyte mitogenic activity. The purpose of this study was to explore whether ACs affect the role of IL-2 underlying immunomodulatory functions. Material and Methods Irradiated human ACs from osteoarthritis donors were used. Third-party ACs were added to the mixed lymphocyte reaction (MLR) with or without recombinant human IL-2 (rhIL-2), and the levels of IL-2 and the soluble form of the IL-2 receptor α (sIL-2Rα) protein in supernatant were measured by enzyme-linked immunosorbent assay. Recombinant human IL-2 (rhIL-2) was also added to the MLR. To detect the expression of IL-2 receptor α (CD25) on lymphocytes in the MLR, flow cytometric analysis was performed. Last, ACs and allogeneic activated CD4+ T cell were co-cultured, and the expression of CD25 on activated T cells was examined by flow cytometry. Results Third-party ACs significantly inhibited the MLR and reduced the level of sIL-2Rα in a dose-dependent manner, but did not affect the concentration of IL-2. Exogenous rhIL-2 accelerated MLR but did not rescue the inhibitory effect of ACs. ACs inhibited the expression of CD25 on activated CD4+ T cells. Discussion Our results showed that third-party ACs inhibited the proliferation of allogeneic activated lymphocytes, thereby inhibiting production sIL-2Rα, although ACs did not affect IL-2 secretion from lymphocytes. Also, ACs inhibited CD25 expression on activated CD4+ T cells. Thus, ACs inhibited the immune response of allogeneic lymphocytes by inducing IL-2 nonresponsiveness.

scholarly journals SLFN2 protection of tRNAs from stress-induced cleavage is essential for T cell–mediated immunity

Science ◽  
2021 ◽  
Vol 372 (6543) ◽  
pp. eaba4220 ◽  
Author(s):  
Tao Yue ◽  
Xiaoming Zhan ◽  
Duanwu Zhang ◽  
Ruchi Jain ◽  
Kuan-wen Wang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Interleukin 2 ◽  
Cell Receptor ◽  
Cell Mediated Immunity ◽  
Activated T Cells ◽  
Granule Formation

Reactive oxygen species (ROS) increase in activated T cells because of metabolic activity induced to support T cell proliferation and differentiation. We show that these ROS trigger an oxidative stress response that leads to translation repression. This response is countered by Schlafen 2 (SLFN2), which directly binds transfer RNAs (tRNAs) to protect them from cleavage by the ribonuclease angiogenin. T cell–specific SLFN2 deficiency results in the accumulation of tRNA fragments, which inhibit translation and promote stress-granule formation. Interleukin-2 receptor β (IL-2Rβ) and IL-2Rγ fail to be translationally up-regulated after T cell receptor stimulation, rendering SLFN2-deficient T cells insensitive to interleukin-2’s mitogenic effects. SLFN2 confers resistance against the ROS-mediated translation-inhibitory effects of oxidative stress normally induced by T cell activation, permitting the robust protein synthesis necessary for T cell expansion and immunity.

Costimulatory action of glycoinositolphospholipids from Trypanosoma cruzi: increased interleukin 2 secretion and induction of nuclear translocation of the nuclear factor of activated T cells 1

1999 ◽  
Vol 13 (12) ◽  
pp. 1627-1636 ◽  
Author(s):  
Maria Bellio ◽  
Ana‐Carolina S. C. Oliveira ◽  
Claudia S. Mermelstein ◽  
Marcia A. M. Capella ◽  
João P. B. Viola ◽  
...  
Keyword(s):  
T Cells ◽  
Trypanosoma Cruzi ◽  
Nuclear Translocation ◽  
Interleukin 2 ◽  
Nuclear Factor ◽  
Activated T Cells

B-cell antigen receptor activates transcription factors NFAT (nuclear factor of activated T-cells) and NF-κB (nuclear factor κB) via a mechanism that involves diacylglycerol

2004 ◽  
Vol 32 (1) ◽  
pp. 113-115 ◽  
Author(s):  
P. Antony ◽  
J.B. Petro ◽  
G. Carlesso ◽  
N.P. Shinners ◽  
J. Lowe ◽  
...  
Keyword(s):  
T Cells ◽  
Transcription Factors ◽  
B Cell ◽  
Antigen Receptor ◽  
Nuclear Factor Κb ◽  
B Cell Antigen Receptor ◽  
Nuclear Factor ◽  
Activated T Cells ◽  
Cell Antigen Receptor ◽  
Cell Antigen

Engagement of the B-cell antigen receptor (BCR) induces the activation of various transcription factors, including NFAT (nuclear factor of activated T-cells) and NF-κB (nuclear factor κB), which participate in long-term biological responses such as proliferation, survival and differentiation of B-lymphocytes. We addressed the biochemical basis of this process using the DT40 chicken B-cell lymphoma. We discovered that Bruton's tyrosine kinase (BTK) and phospholipase C-γ2 (PLC-γ2) are required to activate NFAT and NF-κB, and to produce the lipid second messenger diacylglycerol in response to BCR cross-linking. Therefore the functional integrity of the BTK/PLC-γ2/diacylglycerol signalling axis is crucial for BCR-directed activation of both transcription factors NFAT and NF-κB.

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