scholarly journals Novel NFAT sites that mediate activation of the interleukin-2 promoter in response to T-cell receptor stimulation.

1995 ◽  
Vol 15 (11) ◽  
pp. 6299-6310 ◽  
Author(s):  
J W Rooney ◽  
Y L Sun ◽  
L H Glimcher ◽  
T Hoey
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
Interleukin 2 ◽  
Cell Receptor ◽  
Receptor Stimulation ◽  
Activated T Cells ◽  
Diverse Range ◽  
Dnase I Footprinting ◽  
Responsive Element ◽  
Insight Into

The transcription factors NFAT and AP-1 have been shown to be essential for inducible interleukin-2 (IL-2) expression in activated T cells. NFAT has been previously reported to bind to two sites in the IL-2 promoter: in association with AP-1 at the distal antigen response element at -280 and at -135. On the basis of DNase I footprinting with recombinant NFAT and AP-1 proteins, gel shift assays, and transfection experiments, we have identified three additional NFAT sites in the IL-2 promoter. Strikingly, all five NFAT sites are essential for the full induction of promoter activity in response to T-cell receptor stimulation. Four of the five NFAT sites are part of composite elements able to bind AP-1 in association with NFAT. These sites display a diverse range of cooperativity and interdependency on NFAT and AP-1 proteins for binding. One of the NFAT sites directly overlaps the CD28-responsive element. We present evidence that CD28 inducibility is conferred by the AP-1 component in NFAT-AP-1 composite elements. These findings provide further insight into the mechanisms involved in the regulation of the IL-2 promoter.

scholarly journals Discrete Generation of Superoxide and Hydrogen Peroxide by T Cell Receptor Stimulation

2002 ◽  
Vol 195 (1) ◽  
pp. 59-70 ◽  
Author(s):  
Satish Devadas ◽  
Luba Zaritskaya ◽  
Sue Goo Rhee ◽  
Larry Oberley ◽  
Mark S. Williams
Keyword(s):  
Hydrogen Peroxide ◽  
T Cell ◽  
T Cell Receptor ◽  
Superoxide Anion ◽  
Fas Ligand ◽  
Interleukin 2 ◽  
Cell Receptor ◽  
Activated T Cells ◽  
Tcr Signals ◽  
Hydrogen Peroxide Generation

Receptor-stimulated generation of reactive oxygen species (ROS) has been shown to regulate signal transduction, and previous studies have suggested that T cell receptor (TCR) signals may involve or be sensitive to ROS. In this study, we have shown for the first time that TCR cross-linking induced rapid (within 15 min) generation of both hydrogen peroxide and superoxide anion, as defined with oxidation-sensitive dyes, selective pharmacologic antioxidants, and overexpression of specific antioxidant enzymes. Furthermore, the data suggest the novel observation that superoxide anion and hydrogen peroxide are produced separately by distinct TCR-stimulated pathways. Unexpectedly, TCR-stimulated activation of the Fas ligand (FasL) promoter and subsequent cell death was dependent upon superoxide anion, but independent of hydrogen peroxide, while nuclear factor of activated T cells (NFAT) activation or interleukin 2 transcription was independent of all ROS. Anti-CD3 induced phosphorylation of extracellular signal–regulated kinase (ERK)1/2 required hydrogen peroxide generation but was unaffected by superoxide anion. Thus, antigen receptor signaling induces generation of discrete species of oxidants that selectively regulate two distinct redox sensitive pathways, a proapoptotic (FasL) and a proliferative pathway (ERK).

Responses to T cell receptor/CD3 and interleukin-2 receptor stimulation are altered in T cells from B cell non-hodgkin's lymphomas

1995 ◽  
Vol 41 (3) ◽  
pp. 175-184
Author(s):  
Seiji Kudoh ◽  
Qiu Wang ◽  
Oscar F. Hidalgo ◽  
Pat Rayman ◽  
Raymond R. Tubbs ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
T Cell Receptor ◽  
Interleukin 2 ◽  
Cell Receptor ◽  
Receptor Stimulation ◽  
Interleukin 2 Receptor ◽  
Hodgkin's Lymphomas

Responses to T cell receptor/CD3 and interleukin-2 receptor stimulation are altered in T cells from B cell non-Hodgkin?s lymphomas

1995 ◽  
Vol 41 (3) ◽  
pp. 175-184 ◽  
Author(s):  
Seiji Kudoh ◽  
Q. Wang ◽  
Oscar F. Hidalgo ◽  
P. Rayman ◽  
Raymond R. Tubbs ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
T Cell Receptor ◽  
Interleukin 2 ◽  
Cell Receptor ◽  
Receptor Stimulation ◽  
Interleukin 2 Receptor

scholarly journals T-cell receptor stimulation elicits an early phase of activation and a later phase of deactivation of the transcription factor NFAT1.

1996 ◽  
Vol 16 (7) ◽  
pp. 3945-3954 ◽  
Author(s):  
C Loh ◽  
J A Carew ◽  
J Kim ◽  
P G Hogan ◽  
A Rao
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Immunosuppressive Drug ◽  
Free Calcium ◽  
Receptor Stimulation ◽  
Activated T Cells ◽  
Phosphorylated Form ◽  
Later Phase

We show here that NFAT1 is rapidly activated, then slowly deactivated, by stimulation of T cells through their antigen receptor. Within minutes of T-cell receptor stimulation, NFAT1 is dephosphorylated, translocates from the cytoplasm into the nucleus, and shows an increase in its ability to bind to DNA. These changes are dependent on calcium mobilization and calcineurin activation, since they are also elicited by ionomycin and are blocked by the immunosuppressive drug cyclosporin A. After several hours of T-cell receptor stimulation, the majority of the NFAT1 in the cell reverts to its original phosphorylated form, reappears in the cytoplasm, and again displays a low affinity for DNA. Deactivation of NFAT1 is facilitated by phorbol 12-myristate 13-acetate and inhibitors of capacitative calcium entry and most likely reflects the slow return of intracellular free calcium concentrations towards resting levels. Our results suggest that calcineurin-dependent signalling pathways mediate the early activation of NFAT1, while phorbol 12-myristate 13-acetate-dependent feedback pathways contribute to the late deactivation. Persistent NFAT-dependent cytokine gene transcription in activated T cells may be mediated by other NFAT family proteins in addition to NFAT1 during the immune response.

scholarly journals RasGRF2, a Guanosine Nucleotide Exchange Factor for Ras GTPases, Participates in T-Cell Signaling Responses

2007 ◽  
Vol 27 (23) ◽  
pp. 8127-8142 ◽  
Author(s):  
Sergio Ruiz ◽  
Eugenio Santos ◽  
Xosé R. Bustelo
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Signaling ◽  
Phospholipase C ◽  
T Cell Receptor ◽  
Interleukin 2 ◽  
Cell Receptor ◽  
T Cell Signaling ◽  
Activated T Cells ◽  
Exchange Factor

ABSTRACT The Ras pathway is critical for the development and function of T lymphocytes. The stimulation of this GTPase in T cells occurs primarily through the Vav1- and phospholipase C-γ1-dependent activation of RasGRP1, a diacylglycerol-responsive Ras GDP/GTP exchange factor. Here, we show that a second exchange factor, RasGRF2, also participates in T-cell signaling. RasGRF2 is expressed in T cells, translocates to immune synapses, activates Ras, and stimulates the transcriptional factor NF-AT (nuclear factor of activated T cells) through Ras- and phospholipase C-γ1-dependent routes. T-cell receptor-, Vav1-, and Ca2+-elicited pathways synergize with RasGRF2 for NF-AT stimulation. The analysis of RasGRF2-deficient mice indicates that this protein is required for the induction of bona fide NF-AT targets such as the cytokines tumor necrosis factor alpha and interleukin 2, while it plays minor roles in Ras activation itself. The comparison of lymphocytes from Vav1 −/−, Rasgrf2 −/−, and Vav1 −/−; Rasgrf2 −/− mice demonstrates that the RasGRF2 pathway cooperates with the Vav1/RasGRP1 route in the blasting transformation and proliferation of mature T cells. These results identify RasGRF2 as an additional component of the signaling machinery involved in T-cell receptor- and NF-AT-mediated immune responses.

scholarly journals T cell receptor-dependent cell death of T cell hybridomas mediated by the CD30 cytoplasmic domain in association with tumor necrosis factor receptor-associated factors.

1996 ◽  
Vol 183 (2) ◽  
pp. 669-674 ◽  
Author(s):  
S Y Lee ◽  
C G Park ◽  
Y Choi
Keyword(s):  
Cell Death ◽  
T Cell ◽  
Tumor Necrosis Factor ◽  
T Cell Receptor ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Receptor ◽  
Cell Receptor ◽  
Cytoplasmic Domain ◽  
Activated T Cells ◽  
Necrosis Factor

CD30 is a member of the tumor necrosis factor superfamily and a surface marker for Hodgkin's disease. Normal activated T cells and several virally transformed T or B cell lines also show CD30 expression. The interaction of CD30 with its ligand induces cell death or proliferation, depending on the cell type. In this report we characterize the signals mediated by the intracellular domain of CD30 and show that, in combination with signal(s) transduced by the T cell receptor, the multimerization of CD30 cytoplasmic domain induces Fas(CD95)-independent cell death in T cell hybridomas. Deletion analysis shows that the COOH-terminal 66 amino acids of CD30 are required to induce cell death. Using the yeast two-hybrid system, we have identified that the same region of CD30 interacts with tumor necrosis factor receptor-associated factor (TRAF)1 and TRAF2. These results indicate that TRAF1 and/or TRAF2 play an important role in cell death in addition to their previously identified roles in cell proliferation.

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