Fas ligand mediates activation-induced cell death in human T lymphocytes.

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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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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Engagement of the α2β1 integrin inhibits Fas ligand expression and activation-induced cell death in T cells in a focal adhesion kinase-dependent manner

Blood ◽

10.1182/blood.v95.6.2044 ◽

2000 ◽

Vol 95 (6) ◽

pp. 2044-2051 ◽

Cited By ~ 45

Author(s):

Fawzi Aoudjit ◽

Kristiina Vuori

Keyword(s):

Immune Response ◽

T Cells ◽

Cell Death ◽

T Cell ◽

Focal Adhesion Kinase ◽

Focal Adhesion ◽

Fas Ligand ◽

Integrin Signaling ◽

Activation Induced Cell Death ◽

Fas L

Abstract T-cell receptor (TCR)-mediated apoptosis, also known as activation-induced cell death (AICD), plays an important role in the control of immune response and in the development of T-cell repertoire. Mechanistically, AICD has been largely attributed to the interaction of Fas ligand (Fas-L) with its cell surface receptor Fas in activated T cells. Signal transduction mediated by the integrin family of cell adhesion receptors has been previously shown to modulate apoptosis in a number of different cell types; in T cells, integrin signaling is known to be important in cellular response to antigenic challenge by providing a co-stimulatory signal for TCR. In this study we demonstrate that signaling via the collagen receptor 2β1 integrin specifically inhibits AICD by inhibiting Fas-L expression in activated Jurkat T cells. Engagement of the 2β1 integrin with monoclonal antibodies or with type I collagen, a cognate ligand for 2β1, reduced anti-CD3 and PMA/ionomycin-induced cell death by 30% and 40%, respectively, and the expression of Fas-L mRNA by 50%. Further studies indicated that the 2β1-mediated inhibition of AICD and Fas-L expression required the focal adhesion kinase FAK, a known component in the integrin signaling pathways. These results suggest a role for the 2β1 integrin in the control of homeostasis of immune response and T-cell development.

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T Cell Receptor-induced Activation and Apoptosis In Cycling Human T Cells Occur throughout the Cell Cycle

Molecular Biology of the Cell ◽

10.1091/mbc.10.12.4441 ◽

1999 ◽

Vol 10 (12) ◽

pp. 4441-4450 ◽

Cited By ~ 15

Author(s):

Michael Karas ◽

Tal Z. Zaks ◽

Liu JL ◽

Derek LeRoith

Keyword(s):

Cell Cycle ◽

T Cells ◽

Cell Death ◽

T Cell ◽

T Cell Receptor ◽

Fas Ligand ◽

Cell Receptor ◽

Receptor Activation ◽

Activation Induced Cell Death ◽

Human T Cells

Previous studies have found conflicting associations between susceptibility to activation-induced cell death and the cell cycle in T cells. However, most of the studies used potentially toxic pharmacological agents for cell cycle synchronization. A panel of human melanoma tumor-reactive T cell lines, a CD8+ HER-2/neu-reactive T cell clone, and the leukemic T cell line Jurkat were separated by centrifugal elutriation. Fractions enriched for the G0–G1, S, and G2–M phases of the cell cycle were assayed for T cell receptor-mediated activation as measured by intracellular Ca2+flux, cytolytic recognition of tumor targets, and induction of Fas ligand mRNA. Susceptibility to apoptosis induced by recombinant Fas ligand and activation-induced cell death were also studied. None of the parameters studied was specific to a certain phase of the cell cycle, leading us to conclude that in nontransformed human T cells, both activation and apoptosis through T cell receptor activation can occur in all phases of the cell cycle.

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Differential Susceptibility of Naïve and Activated Human γδ T Cells to Activation-Induced Cell Death by T-Cell Receptor Cross-Linking

Molecular Medicine ◽

10.1007/bf03401870 ◽

2001 ◽

Vol 7 (9) ◽

pp. 636-643 ◽

Cited By ~ 9

Author(s):

Yunn-Hwen Gan ◽

Shirley S. N. Lui ◽

Miroslav Malkovsky

Keyword(s):

T Cells ◽

Cell Death ◽

T Cell ◽

T Cell Receptor ◽

Differential Susceptibility ◽

Γδ T Cells ◽

Cell Receptor ◽

Cross Linking ◽

Activation Induced Cell Death

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The Caspase 8 Inhibitor c-FLIPL Modulates T-Cell Receptor-Induced Proliferation but Not Activation-Induced Cell Death of Lymphocytes

Molecular and Cellular Biology ◽

10.1128/mcb.22.15.5419-5433.2002 ◽

2002 ◽

Vol 22 (15) ◽

pp. 5419-5433 ◽

Cited By ~ 109

Author(s):

Susanne M. A. Lens ◽

Takao Kataoka ◽

Karen A. Fortner ◽

Antoine Tinel ◽

Isabel Ferrero ◽

...

Keyword(s):

T Cells ◽

Cell Death ◽

T Cell ◽

T Cell Receptor ◽

Death Receptor ◽

Cell Receptor ◽

Caspase 8 ◽

Activation Induced Cell Death

ABSTRACT The caspase 8 inhibitor c-FLIPL can act in vitro as a molecular switch between cell death and growth signals transmitted by the death receptor Fas (CD95). To elucidate its function in vivo, transgenic mice were generated that overexpress c-FLIPL in the T-cell compartment (c-FLIPL Tg mice). As anticipated, FasL-induced apoptosis was inhibited in T cells from the c-FLIPL Tg mice. In contrast, activation-induced cell death of T cells in c-FLIPL Tg mice was unaffected, suggesting that this deletion process can proceed in the absence of active caspase 8. Accordingly, c-FLIPL Tg mice differed from Fas-deficient mice by showing no accumulation of B220+ CD4− CD8− T cells. However, stimulation of T lymphocytes with suboptimal doses of anti-CD3 or antigen revealed increased proliferative responses in T cells from c-FLIPL Tg mice. Thus, a major role of c-FLIPL in vivo is the modulation of T-cell proliferation by decreasing the T-cell receptor signaling threshold.

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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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Inhibition of Superoxide Generation upon T-Cell Receptor Engagement Rescues Mart-127-35–Reactive T Cells from Activation-Induced Cell Death

Cancer Research ◽

10.1158/0008-5472.can-09-1176 ◽

2009 ◽

Vol 69 (15) ◽

pp. 6282-6289 ◽

Cited By ~ 23

Author(s):

Håkan Norell ◽

Telma Martins da Palma ◽

Aaron Lesher ◽

Navtej Kaur ◽

Meenal Mehrotra ◽

...

Keyword(s):

T Cells ◽

Cell Death ◽

T Cell ◽

T Cell Receptor ◽

Cell Receptor ◽

Superoxide Generation ◽

Activation Induced Cell Death

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Regulation of Fas-mediated immune homeostasis by an activation-induced protein, Cyclon

Blood ◽

10.1182/blood-2008-11-189118 ◽

2009 ◽

Vol 114 (7) ◽

pp. 1355-1365 ◽

Cited By ~ 11

Author(s):

Shella Saint Fleur ◽

Akemi Hoshino ◽

Kimie Kondo ◽

Takeshi Egawa ◽

Hodaka Fujii

Keyword(s):

T Cells ◽

Cell Death ◽

Critical Role ◽

Cell Receptor ◽

Surface Proteins ◽

Immune Homeostasis ◽

Activated T Cells ◽

Transgenic Expression ◽

Activation Induced Cell Death ◽

Inducible Protein

Abstract Activation-induced cell death (AICD) plays an essential role in the contraction of activated T cells after eradication of pathogen. Fas (APO-1/CD95) is one of the key cell surface proteins that mediate AICD in CD4+ and CD8+ T cells. Despite its prime importance in cell death, regulation of Fas expression in T cells is poorly understood. Here we show that Cyclon, a newly identified cytokine-inducible protein, is induced in T cells on T-cell receptor ligation and important for immune homeostasis. Transgenic expression of Cyclon ameliorated autoimmune phenotype in mice lacking subunits of IL-2R. Transgenic expression of Cyclon markedly enhanced AICD through increased expression of Fas whose expression is essential for Cyclon action. Finally, we demonstrated that activated but not resting CD4+ T cells with targeted deletion of a Cyclon allele show reduced AICD and expression of Fas, indicating a critical role of Cyclon in Fas expression in activated T cells. We think that our data provide insight into expression regulation of Fas in T cells.

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Cytotoxicity of fresh NK1.1+ T cell receptor alpha/beta+ thymocytes against a CD4+8+ thymocyte population associated with intact Fas antigen expression on the target.

Journal of Experimental Medicine ◽

10.1084/jem.180.2.423 ◽

1994 ◽

Vol 180 (2) ◽

pp. 423-432 ◽

Cited By ~ 97

Author(s):

H Arase ◽

N Arase ◽

Y Kobayashi ◽

Y Nishimura ◽

S Yonehara ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Receptor ◽

Fas Ligand ◽

Physiological Role ◽

Cell Receptor ◽

Target Cells ◽

Fas Antigen ◽

Alpha Beta ◽

T Lymphoma

Recent studies have revealed that 10-20% of CD4+8- or CD4-8- thymocyte populations contain NK1.1+ T cell receptor (TCR)-alpha/beta+ cells. This subpopulation shows characteristics that are different from NK1.1- CD4+ or NK1.1- CD8+ T cells and seems to have developed in a manner different from NK1.1- T cells. Although extensive studies have been performed on the NK1.1+ TCR-alpha/beta+ thymocytes, the physiological role of the NK1.1+ TCR-alpha/beta+ thymocytes has been totally unclear. In the present study, we found that freshly isolated NK1.1+ TCR-alpha/beta+ thymocytes, but neither whole thymocytes nor lymph node T cells, directly killed CD4+8+ thymocytes from normal syngeneic or allogeneic mice by using a long-term cytotoxic assay in which flow cytometry was used to detect the cytotoxicity. However, only weak cytotoxicity was detected against thymocytes from lpr mice on which the Fas antigen that transduces signals for apoptosis into the cells is not expressed. Furthermore, the NK1.1+ TCR-alpha/beta+ thymocytes exhibited high cytotoxicity against T lymphoma targets transfected with fas genes as compared with the parental T lymphoma targets or target cells transfected with mutated fas genes, which lack the function of transducing signals. On the other hand, NK1.1+ effector thymocytes from gld mice that carry a point mutation in Fas ligand did not kill thymocyte targets from normal mice. The present findings, thus, consistently suggest that the NK1.1+ TCR-alpha/beta+ thymocytes kill a subpopulation among CD4+8+ thymocytes via Fas antigen and in this way regulate generation of T lineage cells in the thymus.

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