Cutting Edge: The Class II Transactivator Prevents Activation-Induced Cell Death by Inhibiting Fas Ligand Gene Expression

A significant proportion of previously activated human T cells undergo apoptosis when triggered through the CD3/T cell receptor complex, a process termed activation-induced cell death (AICD). Ligation of Fas on activated T cells by either Fas antibodies or recombinant human Fas-ligand (Fas-L) also results in cytolysis. We demonstrate that these two pathways of apoptosis are causally related. Stimulation of previously activated T cells resulted in the expression of Fas-L mRNA and lysis of Fas-positive target cells. Fas-L antagonists inhibited AICD of T cell clones and staphylococcus enterotoxin B (SEB)-specific T cell lines. The data indicate AICD in previously stimulated T cells is mediated by Fas/Fas-L interactions.

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Inhibition of activation-induced death of dendritic cells and enhancement of vaccine efficacy via blockade of MINOR

Blood ◽

10.1182/blood-2008-08-176354 ◽

2009 ◽

Vol 113 (13) ◽

pp. 2906-2913 ◽

Cited By ~ 20

Author(s):

Tianhong Wang ◽

Qiong Jiang ◽

Camie Chan ◽

Kevin S. Gorski ◽

Erin McCadden ◽

...

Keyword(s):

Gene Expression ◽

Cell Death ◽

Dendritic Cells ◽

Vaccine Efficacy ◽

Lentiviral Vector ◽

Ex Vivo ◽

Orphan Receptor ◽

Activation Induced Cell Death ◽

Dc Vaccines ◽

Interfering Rna

Abstract Activation of dendritic cells (DCs) leads to cell maturation, which is accompanied by a regulated pattern of gene expression changes. Two significant and contradictory consequences of DC activation are that, although activation is necessary for maximal T-cell stimulation, it also leads to the initiation of gene expression that results ultimately in cell death. We have identified a gene, MINOR (mitogen-inducible nuclear orphan receptor), that becomes highly up-regulated on activation and whose expression leads to apoptosis in mature DCs. MINOR is a member of the Nur77 family of nuclear orphan receptors, which includes Nur77 and Nurr1. Although Nur77 and Nurr1 are expressed in macrophages and DCs, their expression levels do not change on DC activation. We thus tested the hypothesis that induction of MINOR would lead to an activation-induced cell death in DCs and that its inhibition would increase the lifespan of DCs and improve their vaccine efficacy. To block natural expression of MINOR by DCs, we generated a lentiviral vector that expresses a small interfering RNA. Our results indicate that blockade of MINOR expression dramatically decreases apoptosis in DCs and suggest that this approach may be a novel means to improve the potency of ex vivo–generated DC vaccines.

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Glucocorticoids inhibit activation-induced cell death (AICD) via direct DNA-dependent repression of the CD95 ligand gene by a glucocorticoid receptor dimer

Blood ◽

10.1182/blood-2004-11-4390 ◽

2005 ◽

Vol 106 (2) ◽

pp. 617-625 ◽

Cited By ~ 58

Author(s):

Sven Baumann ◽

Anja Dostert ◽

Natalia Novac ◽

Anton Bauer ◽

Wolfgang Schmid ◽

...

Keyword(s):

T Cells ◽

Cell Death ◽

T Cell ◽

Glucocorticoid Receptor ◽

Fas Ligand ◽

Regulatory Elements ◽

Activated T Cells ◽

Activation Induced Cell Death

Abstract Glucocorticoids (GCs) play an important role in the regulation of peripheral T-cell survival. Their molecular mechanism of action and the question of whether they have the ability to inhibit apoptosis in vivo, however, are not fully elucidated. Signal transduction through the glucocorticoid receptor (GR) is complex and involves different pathways. Therefore, we used mice with T-cell-specific inactivation of the GR as well as mice with a function-selective mutation in the GR to determine the signaling mechanism. Evidence is presented for a functional role of direct binding of the GR to 2 negative glucocorticoid regulatory elements (nGREs) in the CD95 (APO-1/Fas) ligand (L) promoter. Binding of GRs to these nGREs reduces activation-induced CD95L expression in T cells. These in vitro results are fully supported by data obtained in vivo. Administration of GCs to mice leads to inhibition of activation-induced cell death (AICD). Thus, GC-mediated inhibition of CD95L expression of activated T cells might contribute to the anti-inflammatory function of steroid drugs. (Blood. 2005;106:617-625)

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Non-apoptotic Signaling Pathways Activated by Soluble Fas Ligand in Serum-starved Human Fibroblasts

Journal of Biological Chemistry ◽

10.1074/jbc.m107385200 ◽

2001 ◽

Vol 276 (50) ◽

pp. 47100-47106 ◽

Cited By ~ 72

Author(s):

Jin-Hyung Ahn ◽

Sun-Mi Park ◽

Ho-Sung Cho ◽

Myung-Shik Lee ◽

Jong-Bok Yoon ◽

...

Keyword(s):

Gene Expression ◽

Cell Death ◽

Fas Ligand ◽

Human Fibroblasts ◽

Serum Starvation ◽

Protein Synthesis Inhibitor ◽

Caspase 8 ◽

Complete Medium ◽

Soluble Fas ◽

Soluble Fas Ligand

Many Fas-expressing cells do not undergo cell death upon Fas stimulation. In the normal human diploid cell line GM6112, the addition of soluble Fas ligand (sFasL) leads to morphological signs of cell death in less than 1% of cells. Treatment of serum-starved GM6112 fibroblasts with sFasL resulted in a rapid and transient phosphorylation of ERK1/2 without a significant increase in JNK and p38 activities. Unless co-treated with the protein synthesis inhibitor anisomycin, sFasL did not show gene-inducing activity in cells maintained in complete medium. However, when cells were serum-starved for 4 days, treatment with sFasL alone induced interleukin-6 gene expression and, less strongly, interleukin-8 gene expression. Sensitization of the gene-inducing activity by serum starvation correlated with NF-κB activation by sFasL. Furthermore, we found that the expression of FADD and caspase-8 was significantly reduced in serum-starved cells, whereas the level of cFLIP remained unchanged. Transfection of GM6112 cells with the antisense caspase-8 expression construct sensitized cells toward sFasL-induced NF-κB-dependent reporter activation. Our results support the notion that a change in the ratio of cFLIP and caspase-8 may be responsible for turning on the Fas-activated NF-κB pathway, which otherwise is supplanted by the death-inducing pathway.

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Extreme lymphoproliferative disease and fatal autoimmune thrombocytopenia in FasL and TRAIL double-deficient mice

Blood ◽

10.1182/blood-2009-11-255497 ◽

2010 ◽

Vol 115 (16) ◽

pp. 3258-3268 ◽

Cited By ~ 17

Author(s):

Lisa M. Sedger ◽

Arna Katewa ◽

Ann K. Pettersen ◽

Sarah R. Osvath ◽

Geoff C. Farrell ◽

...

Keyword(s):

T Cells ◽

Cell Death ◽

Fas Ligand ◽

Interferon Γ ◽

Lymphoproliferative Disease ◽

Activation Induced Cell Death ◽

Lymphocyte Homeostasis ◽

Idiopathic Thrombocytopenia Purpura ◽

Follicular B Cells ◽

Necrosis Factor

Abstract To delineate the relative roles of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and Fas ligand in lymphocyte biology and lymphoproliferative disease, we generated mice defective in both molecules. B6.GT mice develop severe polyclonal lymphoproliferative disease because of accumulating CD3+CD4−CD8−B220+ T cells, CD4+ and CD8+ T cells, and follicular B cells, and mice die prematurely from extreme lymphocytosis, thrombocytopenia, and hemorrhage. Accumulating lymphocytes resembled antigen-experienced lymphocytes, consistent with the maximal resistance of B6.GT CD4+ and CD8+ T cell to activation-induced cell death. More specifically, we show that TRAIL contributes to Fas ligand-mediated activation-induced cell death and controls lymphocyte apoptosis in the presence of interferon-γ once antigen stimulation is removed. Furthermore, dysregulated lymphocyte homeostasis results in the production of anti-DNA and rheumatoid factor autoantibodies, as well as antiplatelet IgM and IgG causing thrombocytopenia. Thus, B6.GT mice reveal new roles for TRAIL in lymphocyte homeostasis and autoimmune lymphoproliferative syndromes and are a model of spontaneous idiopathic thrombocytopenia purpura secondary to lymphoproliferative disease.

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Regulation of FAS Ligand Expression during Activation-Induced Cell Death in T Cells by p38 Mitogen-Activated Protein Kinase and C-Jun Nh2-Terminal Kinase

Journal of Experimental Medicine ◽

10.1084/jem.191.6.1017 ◽

2000 ◽

Vol 191 (6) ◽

pp. 1017-1030 ◽

Cited By ~ 67

Author(s):

Jian Zhang ◽

Jian-Xin Gao ◽

Kostantin Salojin ◽

Qing Shao ◽

Marsha Grattan ◽

...

Keyword(s):

T Cells ◽

Cell Death ◽

T Cell ◽

Protein Kinase ◽

P38 Mapk ◽

Fas Ligand ◽

Mitogen Activated Protein Kinase ◽

Fasl Expression ◽

Activation Induced Cell Death ◽

Mitogen Activated Protein

Activation-induced cell death (AICD) is a mechanism of peripheral T cell tolerance that depends upon an interaction between Fas and Fas ligand (FasL). Although c-Jun NH2-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK) may be involved in apoptosis in various cell types, the mode of regulation of FasL expression during AICD in T cells by these two MAPKs is incompletely understood. To investigate the regulatory roles of these two MAPKs, we analyzed the kinetics of TCR-induced p38 MAPK and JNK activity and their regulation of FasL expression and AICD. We report that both JNK and p38 MAPK regulate AICD in T cells. Our data suggest a novel model of T cell AICD in which p38 MAPK acts early to initiate FasL expression and the Fas-mediated activation of caspases. Subsequently, caspases stimulate JNK to further upregulate FasL expression. Thus, p38 MAPK and downstream JNK converge to regulate FasL expression at different times after T cell receptor stimulation to elicit maximum AICD.

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