Resistance of cultured peripheral T cells towards activation-induced cell death involves a lack of recruitment of FLICE (MACH/caspase 8) to the CD95 death-inducing signaling complex

Abstract Activation-induced cell death (AICD) in T cells is mediated by CD95 ligand (CD95L)/receptor interaction, which has also been implicated in apoptosis induction by some anticancer agents. In this article we show that both anti-CD3-triggering (AICD) and doxorubicin treatment led to the production of a functionally active CD95L in the CD3+/T-cell receptor-positive (TCR+) T leukemia cell line H9. CD95L-expressing H9 cells killed CD95-sensitive J16 or CEM target cells, but not CD95-resistant CEM or J16 cells overexpressing dominant negative FADD (J16/FADD-DN). By immunoprecipitation, CD95L was physically bound to CD95, suggesting that AICD and doxorubicin-induced apoptosis involve CD95L-mediated CD95 aggregation, thereby triggering the CD95 death pathway. CD95 aggregation was associated with the recruitment of FADD and caspase-8 to the CD95 receptor to form the CD95 death-inducing signaling complex (DISC), resulting in caspase-8 activation and cleavage of the effector caspase-3 and PARP. Blocking of the CD95L/receptor interaction by antagonistic antibodies to CD95 or to CD95L also blocked AICD and inhibited the early phase of doxorubicin-induced apoptosis, though cell death induced by doxorubicin eventually proceeded in a CD95-independent manner. These findings may explain some conflicting data on the role of death receptor systems in drug-induced apoptosis. Thus, in cells with an inducible CD95 receptor/ligand system, drug-induced apoptosis may be mediated by CD95L-initiated DISC formation and activation of downstream effector programs similar to AICD in T cells. (Blood. 2000;95:301-308)

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Functional CD95 ligand and CD95 death-inducing signaling complex in activation-induced cell death and doxorubicin-induced apoptosis in leukemic T cells

Blood ◽

10.1182/blood.v95.1.301.001k24_301_308 ◽

2000 ◽

Vol 95 (1) ◽

pp. 301-308 ◽

Cited By ~ 9

Author(s):

Simone Fulda ◽

Gudrun Strauss ◽

Eric Meyer ◽

Klaus-Michael Debatin

Keyword(s):

T Cells ◽

Cell Death ◽

Leukemia Cell Line ◽

Receptor Interaction ◽

Caspase 8 ◽

Drug Induced ◽

Signaling Complex ◽

Cd95 Ligand ◽

Activation Induced Cell Death ◽

Induced Apoptosis

Activation-induced cell death (AICD) in T cells is mediated by CD95 ligand (CD95L)/receptor interaction, which has also been implicated in apoptosis induction by some anticancer agents. In this article we show that both anti-CD3-triggering (AICD) and doxorubicin treatment led to the production of a functionally active CD95L in the CD3+/T-cell receptor-positive (TCR+) T leukemia cell line H9. CD95L-expressing H9 cells killed CD95-sensitive J16 or CEM target cells, but not CD95-resistant CEM or J16 cells overexpressing dominant negative FADD (J16/FADD-DN). By immunoprecipitation, CD95L was physically bound to CD95, suggesting that AICD and doxorubicin-induced apoptosis involve CD95L-mediated CD95 aggregation, thereby triggering the CD95 death pathway. CD95 aggregation was associated with the recruitment of FADD and caspase-8 to the CD95 receptor to form the CD95 death-inducing signaling complex (DISC), resulting in caspase-8 activation and cleavage of the effector caspase-3 and PARP. Blocking of the CD95L/receptor interaction by antagonistic antibodies to CD95 or to CD95L also blocked AICD and inhibited the early phase of doxorubicin-induced apoptosis, though cell death induced by doxorubicin eventually proceeded in a CD95-independent manner. These findings may explain some conflicting data on the role of death receptor systems in drug-induced apoptosis. Thus, in cells with an inducible CD95 receptor/ligand system, drug-induced apoptosis may be mediated by CD95L-initiated DISC formation and activation of downstream effector programs similar to AICD in T cells. (Blood. 2000;95:301-308)

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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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Enhanced activation-induced cell death as a mechanism of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced immunotoxicity in peripheral T cells

Toxicology ◽

10.1016/s0300-483x(01)00391-2 ◽

2001 ◽

Vol 165 (1) ◽

pp. 51-63 ◽

Cited By ~ 31

Author(s):

Iris A. Camacho ◽

Mona R. Hassuneh ◽

Mitzi Nagarkatti ◽

Prakash S. Nagarkatti

Keyword(s):

T Cells ◽

Cell Death ◽

Activation Induced Cell Death ◽

Peripheral T Cells ◽

Tetrachlorodibenzo P Dioxin

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Cryo-EM structural analysis of FADD:Caspase-8 complexes defines the catalytic dimer architecture for co-ordinated control of cell fate

Nature Communications ◽

10.1038/s41467-020-20806-9 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Joanna L. Fox ◽

Michelle A. Hughes ◽

Xin Meng ◽

Nikola A. Sarnowska ◽

Ian R. Powley ◽

...

Keyword(s):

Cell Death ◽

Structural Analysis ◽

Cell Fate ◽

Catalytic Domain ◽

Caspase 8 ◽

Type I ◽

Signaling Complex ◽

Catalytic Domains ◽

Regulated Cell Death ◽

Death Effector

AbstractRegulated cell death is essential in development and cellular homeostasis. Multi-protein platforms, including the Death-Inducing Signaling Complex (DISC), co-ordinate cell fate via a core FADD:Caspase-8 complex and its regulatory partners, such as the cell death inhibitor c-FLIP. Here, using electron microscopy, we visualize full-length procaspase-8 in complex with FADD. Our structural analysis now reveals how the FADD-nucleated tandem death effector domain (tDED) helical filament is required to orientate the procaspase-8 catalytic domains, enabling their activation via anti-parallel dimerization. Strikingly, recruitment of c-FLIPS into this complex inhibits Caspase-8 activity by altering tDED triple helix architecture, resulting in steric hindrance of the canonical tDED Type I binding site. This prevents both Caspase-8 catalytic domain assembly and tDED helical filament elongation. Our findings reveal how the plasticity, composition and architecture of the core FADD:Caspase-8 complex critically defines life/death decisions not only via the DISC, but across multiple key signaling platforms including TNF complex II, the ripoptosome, and RIPK1/RIPK3 necrosome.

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

Journal of Experimental Medicine ◽

10.1084/jem.181.1.71 ◽

1995 ◽

Vol 181 (1) ◽

pp. 71-77 ◽

Cited By ~ 625

Author(s):

M R Alderson ◽

T W Tough ◽

T Davis-Smith ◽

S Braddy ◽

B Falk ◽

...

Keyword(s):

T Cells ◽

Cell Death ◽

T Cell ◽

Fas Ligand ◽

Significant Proportion ◽

Cell Receptor ◽

Target Cells ◽

Activated T Cells ◽

Activation Induced Cell Death ◽

Fas L

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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