scholarly journals Regulation of Transcription Factor NFAT by ADP-Ribosylation

2008 ◽  
Vol 28 (9) ◽  
pp. 2860-2871 ◽  
Author(s):  
Opeyemi A. Olabisi ◽  
Noemi Soto-Nieves ◽  
Edward Nieves ◽  
Teddy T. C. Yang ◽  
XiaoYong Yang ◽  
...  
Keyword(s):  
T Cells ◽  
Transcription Factor ◽  
Interleukin 2 ◽  
Regulation Of Transcription ◽  
Dependent Manner ◽  
Immune Functions ◽  
Genetic Ablation ◽  
Adp Ribosylation ◽  
Parp 1 ◽  
Transcription Factor Nfat

ABSTRACT ADP-ribosylation is a reversible posttranslational modification mediated by poly-ADP-ribose polymerase (PARP). The results of recent studies demonstrate that ADP-ribosylation contributes to transcription regulation. Here, we report that transcription factor NFAT binds to and is ADP-ribosylated by PARP-1 in an activation-dependent manner. Mechanistically, ADP-ribosylation increases NFAT DNA binding. Functionally, NFAT-mediated interleukin-2 (IL-2) expression was reduced in T cells upon genetic ablation or pharmacological inhibition of PARP-1. Parp-1 −/− T cells also exhibit reduced expression of other NFAT-dependent cytokines, such as IL-4. Together, these results demonstrate that ADP-ribosylation mediated by PARP-1 provides a molecular switch to positively regulate NFAT-dependent cytokine gene transcription. These results also imply that, similar to the effect of calcineurin inhibition, PARP-1 inhibition may be beneficial in modulating immune functions.

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 Nonmalignant T cells stimulate growth of T-cell lymphoma cells in the presence of bacterial toxins

Blood ◽  
2006 ◽  
Vol 109 (8) ◽  
pp. 3325-3332 ◽  
Author(s):  
Anders Woetmann ◽  
Paola Lovato ◽  
Karsten W. Eriksen ◽  
Thorbjørn Krejsgaard ◽  
Tord Labuda ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Lines ◽  
Mhc Class Ii ◽  
Interleukin 2 ◽  
Class Ii ◽  
Bacterial Toxins ◽  
Dependent Manner ◽  
Malignant Cells ◽  
T Cell Lines

AbstractBacterial toxins including staphylococcal enterotoxins (SEs) have been implicated in the pathogenesis of cutaneous T-cell lymphomas (CTCLs). Here, we investigate SE-mediated interactions between nonmalignant T cells and malignant T-cell lines established from skin and blood of CTCL patients. The malignant CTCL cells express MHC class II molecules that are high-affinity receptors for SE. Although treatment with SE has no direct effect on the growth of the malignant CTCL cells, the SE-treated CTCL cells induce vigorous proliferation of the SE-responsive nonmalignant T cells. In turn, the nonmalignant T cells enhance proliferation of the malignant cells in an SE- and MHC class II–dependent manner. Furthermore, SE and, in addition, alloantigen presentation by malignant CTCL cells to irradiated nonmalignant CD4+ T-cell lines also enhance proliferation of the malignant cells. The growth-promoting effect depends on direct cell-cell contact and soluble factors such as interleukin-2. In conclusion, we demonstrate that SE triggers a bidirectional cross talk between nonmalignant T cells and malignant CTCL cells that promotes growth of the malignant cells. This represents a novel mechanism by which infections with SE-producing bacteria may contribute to pathogenesis of CTCL.

scholarly journals NF-kappa B as inducible transcriptional activator of the granulocyte-macrophage colony-stimulating factor gene.

1990 ◽  
Vol 10 (3) ◽  
pp. 1281-1286 ◽  
Author(s):  
R Schreck ◽  
P A Baeuerle
Keyword(s):  
T Cells ◽  
Transcription Factor ◽  
T Cell ◽  
Interleukin 2 ◽  
Colony Stimulating Factor ◽  
Nf Kappa B ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

The expression of the gene encoding the granulocyte-macrophage colony-stimulating factor (GM-CSF) is induced upon activation of T cells with phytohemagglutinin and active phorbolester and upon expression of tax1, a transactivating protein of the human T-cell leukemia virus type I. The same agents induce transcription from the interleukin-2 receptor alpha-chain and interleukin-2 genes, depending on promoter elements that bind the inducible transcription factor NF-kappa B (or an NF-kappa B-like factor). We therefore tested the possibility that the GM-CSF gene is also regulated by a cognate motif for the NF-kappa B transcription factor. A recent functional analysis by Miyatake et al. (S. Miyatake, M. Seiki, M. Yoshida, and K. Arai, Mol. Cell. Biol. 8:5581-5587, 1988) described a short promoter region in the GM-CSF gene that conferred strong inducibility by T-cell-activating signals and tax1, but no NF-kappa B-binding motifs were identified. Using electrophoretic mobility shift assays, we showed binding of purified human NF-kappa B and of the NF-kappa B activated in Jurkat T cells to an oligonucleotide comprising the GM-CSF promoter element responsible for mediating responsiveness to T-cell-activating signals and tax1. As shown by a methylation interference analysis and oligonucleotide competition experiments, purified NF-kappa B binds at positions -82 to -91 (GGGAACTACC) of the GM-CSF promoter sequence with an affinity similar to that with which it binds to the biologically functional kappa B motif in the beta interferon promoter (GGGAAATTCC). Two kappa B-like motifs at positions -98 to -108 of the GM-CSF promoter were also recognized but with much lower affinities. Our data provide strong evidence that the expression of the GM-CSF gene following T-cell activation is controlled by binding of the NF-kappa B transcription factor to a high-affinity binding site in the GM-CSF promoter.

scholarly journals Polarization of Allogeneic T-Cell Responses by Influenza Virus-Infected Dendritic Cells

2000 ◽  
Vol 74 (17) ◽  
pp. 7738-7744 ◽  
Author(s):  
Sangkon Oh ◽  
Maryna C. Eichelberger
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Dendritic Cells ◽  
Influenza Virus ◽  
T Cell ◽  
Interleukin 2 ◽  
Dependent Manner ◽  
Ifn Γ ◽  
High Doses ◽  
Type Response

ABSTRACT The developing immune response in the lymph nodes of mice infected with influenza virus has both Th1- and Th2-type characteristics. Modulation of the interactions between antigen-presenting cells and T cells is one mechanism that may alter the quality of the immune response. We have previously shown that the ability of dendritic cells (DC) to stimulate the proliferation of alloreactive T cells is changed by influenza virus due to viral neuraminidase (NA) activity. Here we show that DC infected with influenza virus A/PR/8/34 (PR8) stimulate T cells to produce different types of cytokines in a dose-dependent manner. Optimal amounts of the Th1-type cytokines interleukin-2 (IL-2) and gamma interferon (IFN-γ) were produced from T cells stimulated by DC infected with low doses of PR8, while the Th2-type cytokines IL-4 and IL-10 were produced only in response to DC infected with high doses of PR8. IL-2 and IFN-γ levels corresponded with T-cell proliferation and were dependent on the activity of viral NA on the DC surface. In contrast, IL-4 secretion required the treatment of T cells with NA. Since viral particles were released only from DC that are infected with high doses of PR8, our results suggest that viral NA on newly formed virus particles desialylates T-cell surface molecules to facilitate a Th2-type response. These results suggest that the activity of NA may contribute to the mixed Th-type response observed during influenza virus infection.

scholarly journals Requirement for Transcription Factor NFAT in Interleukin-2 Expression

1999 ◽  
Vol 19 (3) ◽  
pp. 2300-2307 ◽  
Author(s):  
Chi-Wing Chow ◽  
Mercedes Rincón ◽  
Roger J. Davis
Keyword(s):  
Gene Expression ◽  
T Cells ◽  
Transcription Factor ◽  
Nuclear Translocation ◽  
Interleukin 2 ◽  
Inhibitory Effect ◽  
Dominant Negative ◽  
Activated T Cells ◽  
Nfat Activation ◽  
Nfat Transcription Factor

ABSTRACT The nuclear factor of activated T cells (NFAT) transcription factor is implicated in expression of the cytokine interleukin-2 (IL-2). Binding sites for NFAT are located in the IL-2 promoter. Furthermore, pharmacological studies demonstrate that the drug cyclosporin A inhibits both NFAT activation and IL-2 expression. However, targeted disruption of the NFAT1 and NFAT2 genes in mice does not cause decreased IL-2 secretion. The role of NFAT in IL-2 gene expression is therefore unclear. Here we report the construction of a dominant-negative NFAT mutant (dnNFAT) that selectively inhibits NFAT-mediated gene expression. The inhibitory effect of dnNFAT is mediated by suppression of activation-induced nuclear translocation of NFAT. Expression of dnNFAT in cultured T cells caused inhibition of IL-2 promoter activity and decreased expression of IL-2 protein. Similarly, expression of dnNFAT in transgenic mice also caused decreased IL-2 gene expression. These data demonstrate that NFAT is a critical component of the signaling pathway that regulates IL-2 expression.

scholarly journals Interleukin 2 is an Upstream Regulator of CD4+ T Cells From Visceral Leishmaniasis Patients With Therapeutic Potential

2019 ◽  
Vol 220 (1) ◽  
pp. 163-173 ◽  
Author(s):  
Shashi Bhushan Chauhan ◽  
Rebecca Faleiro ◽  
Rajiv Kumar ◽  
Susanna Ng ◽  
Bhawana Singh ◽  
...  
Keyword(s):  
T Cells ◽  
Visceral Leishmaniasis ◽  
Cd4 T Cells ◽  
Leishmania Donovani ◽  
Therapeutic Potential ◽  
Interleukin 2 ◽  
Interferon Γ ◽  
Immune Functions ◽  
T Regulatory Cell ◽  
Upstream Regulator

Abstract Control of visceral leishmaniasis (VL) caused by Leishmania donovani requires interferon-γ production by CD4+ T cells. In VL patients, antiparasitic CD4+ T-cell responses are ineffective for unknown reasons. In this study, we measured the expression of genes associated with various immune functions in these cells from VL patients and compared them to CD4+ T cells from the same patients after drug treatment and from endemic controls. We found reduced GATA3, RORC, and FOXP3 gene expression in CD4+ T cells of VL patients, associated with reduced Th2, Th17, and FOXP3+CD4+ T regulatory cell frequencies in VL patient blood. Interleukin 2 (IL-2) was an important upstream regulator of CD4+ T cells from VL patients, and functional studies demonstrated the therapeutic potential of IL-2 for improving antiparasitic immunity. Together, these results provide new insights into the characteristics of CD4+ T cells from VL patients that can be used to improve antiparasitic immune responses.

scholarly journals Is the Antiproteinuric Effect of Cyclosporine A Independent of Its Immunosuppressive Function in T Cells?

2012 ◽  
Vol 2012 ◽  
pp. 1-6
Author(s):  
Bin Zhang ◽  
Wei Shi
Keyword(s):  
T Cells ◽  
Transcription Factor ◽  
Cyclosporine A ◽  
Immunosuppressive Effect ◽  
Molecular Event ◽  
Podocyte Injury ◽  
Antiproteinuric Effect ◽  
Nfat Activation ◽  
Per Se ◽  
Transcription Factor Nfat

The antiproteinuric effect of cyclosporine A(CsA) has been believed to result from its immunosuppressive effect on the transcription factor NFAT in T cells. However, current evidences supporting this hypothesis are missing. A recent study showed that CsA has a direct antiproteinuric effect on podocytes, suggesting a novel non-immunosuppressive mechanism for CsA's antiproteinuric effect. Conditional NFATc1 activation in podoyctes per se is sufficient to induce proteinuria in mice, indicating that NFAT activation in podocytes is a critical pathogenic molecular event leading to podocyte injury and proteinuria. Meanwhile, evidence showed that TRPC6-mediated Ca2+influx stimulates NFAT-dependent TRPC6 expression. Altogether, these advances in podocyte research indicate that calcineurin-NFAT signal or calcineurin-synaptopodin axis has a direct proteinuric effect on podocytes which raises the possibility of developing specific antiproteinuric drugs that lack the unwanted effects of calcineurin or NFAT inhibition.

Activation-Dependent Expression of an Interleukin-2 Transgene Mediated by Transduction with a Lentiviral Vector Enhances T Cell Functions.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 5273-5273
Author(s):  
Qi Sun ◽  
Karen Chorney ◽  
Carol Stine ◽  
Kenneth G. Lucas
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Lentiviral Vector ◽  
Ex Vivo ◽  
Interleukin 2 ◽  
Immune Functions ◽  
Cell Functions ◽  
Genetically Engineer ◽  
Ifn Γ

Abstract Adoptive T cell immunotherapy (ATCI) is an evolving strategy that explores antigen-specific T cells manipulated ex vivo as therapeutic agents. Although the concept of ATCI has been tested clinically, with success in the treatment of post-transplant EBV induced lymphoproliferative disease, one of the major obstacles hindering its application to other malignancies is the procurement of tumor-specific T cells that possess potent anti-tumor functions even in the inhibitory environment at the tumor sites. This study aims to genetically engineer enriched viral specific T cells for improved immune functions. A self-inactivating lentiviral vector (SIN) CD69p-IL2 was constructed to encode the transgene interleukin-2 (IL2) under the control of a human CD69 promoter (CD69p), and this vector was tested in ex vivo cultivated EBV-specific T cells. SIN vector allows a high degree of autonomy for the internal promoter, and CD69 expression in the T cells is closely associated with T cell activation. Experiments showed that the SIN vectors efficiently transduced EBV-specific T cells, both CD4 and CD8. Furthermore, the newly cloned CD69p exhibited a higher degree of responsiveness to physiological antigen stimulation than the early promoter from the cytomegalovirus (CMVp). In response to stimulation by EBV-infected B cells, the percentage of IL2 expressing cells was 2 fold higher for the activated CD69p-IL2 transduced T cells than the non-transduced, or the CMVp-IL2 transduced, counterparts. In correlation with the stronger IL2 expression, 3 fold more T cells expressed the anti-viral cytokine interferon-γ (IFN-γ) in the CD69p-IL2 transduced T cells than the CMVp-IL2 transduced, and the IFN-γ expression at the single cell level was 2 fold higher in the former, indicating an enhanced functionality. While the culture supernatant from the CMVp-IL2 transduced T cells contained IL2 at a concentration 2000 fold higher than the non-transduced T cells, the IL2 level in the media from the CD69p-IL2 transduced T cells was comparable to that in the control, suggesting the IL2 expression mediated by the CD69p more relevant to T cell functions than the CMVp. These results may serve as a foundation for the further development and clinical application of specific T cells engineered for enhanced immune functions.

Phenotypic and Functional Effects of Perifosine on Dendritic Cells.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4803-4803
Author(s):  
Weihua Song ◽  
Teru Hideshima ◽  
Yu-Tzu Tai ◽  
Kenneth C. Anderson ◽  
Nikhil C. Munshi
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Annexin V ◽  
Antitumor Agent ◽  
Dependent Manner ◽  
Immune Functions ◽  
Akt Inhibitor ◽  
Antitumor Effects

Abstract Perifosine is a synthetic novel alkylphospholipid, a new class of antitumor agent which targets cell membranes and inhibits Akt activation. Perifosine inhibits multiple myeloma (MM) cell growth in vitro and in vivo mouse model. Currently perifosine is under the evaluation of phase II clinical trail in MM. Although perifosine has shown significant direct antitumor effects, its effect on immune system has not yet been clarified. The objective of this study is to evaluate the effects of perifosine on the activity of antigen presenting cells (APCs). Monocyte-derived dendritic cells (DCs) from normal human donors were used as the APCs, and mature DCs were obtained by the treatment of TNF-α and IL-1β. Perifosine was used at the concentrations of 2.5 uM, 5 uM and 10 uM for the treatment with DCs. We first evaluated the effect of perifosine on the survival of DCs. We observed that the perifosine treatment up to 48 hours had no effect on viability (>90%) of DCs, assessed by annexin V and PI staining. Alteration of phenotype by perifosine on DCs was further examined by flow cytometry. Our results demonstrated that with dose-dependent manner, perifosine led to a significant down-regulation of surface antigens on immature DCs at 24 and 48 hours, which associated to costimulation (CD40, CD80 and CD86), antigen presentation (HLA-ABC, HLA-DPQR) and maturation (CD83). However, we did not observed significant effect of perifosine on above surface markers on mature DCs. Since DCs play a crucial role on the regulation of Th1/Th2 immune responses by the production of IL-12, we next evaluated IL-12 secretion by DCs with and without perifosine treatment. Importantly, treatment with perifosine significantly decreased LPS-induced-IL-12 production, compared to untreated DCs (untrt vs. trt = 192.29 vs. 166.23 pg/ml (2.5uM), 111.19 pg/ml (5uM) and 44.886 pg/ml (10uM)) at 24 hours. To assess the effect of perifosine on DCs function on the regulation of T cell responses, we stimulated allogenic T cells with mature DCs with or without the pre-treatment of perifosine. The proliferation assay by 3H-TdR incorporation and IFN-γ production by ELISA indicated perifosine-treated DCs had no significant effect on the regulation of T cells function. Taken together, these results showed that DCs function are influenced by the treatment of perifosine. Our pre-clinical data therefore indicates the need to monitor immune functions in patients under the Akt inhibitor treatment.

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