Melatonin Protects CD4+T Cells from Activation-Induced Cell Death by Blocking NFAT-Mediated CD95 Ligand Upregulation

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)

Download Full-text

Methionine Adenosyltransferase IIA (MAT IIA) Activity And S-adenosylmethionine (Same) Biosynthesis Play A Critical Role In The Survival Of CD4+ T Cells By Regulating Akt Activation And FasL-mediated Activation Induced Cell Death (AICD)

Therapeutic Drug Monitoring ◽

10.1097/00007691-200504000-00112 ◽

2005 ◽

Vol 27 (2) ◽

pp. 235

Author(s):

Tanvi D Modi ◽

Silvia Uriarte ◽

Rashmita Sahoo ◽

Swati Joshi Barve ◽

Craig McClain ◽

...

Keyword(s):

T Cells ◽

Cell Death ◽

Cd4 T Cells ◽

Critical Role ◽

Methionine Adenosyltransferase ◽

Akt Activation ◽

Activation Induced Cell Death

Download Full-text

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)

Download Full-text

Vitamin E inhibits CD95 ligand expression and protects T cells from activation-induced cell death

Journal of Clinical Investigation ◽

10.1172/jci0215073 ◽

2002 ◽

Vol 110 (5) ◽

pp. 681-690 ◽

Cited By ~ 44

Author(s):

Min Li-Weber ◽

Markus A. Weigand ◽

Marco Giaisi ◽

Dorothee Süss ◽

Monika K. Treiber ◽

...

Keyword(s):

T Cells ◽

Cell Death ◽

Vitamin E ◽

Cd95 Ligand ◽

Activation Induced Cell Death ◽

Ligand Expression

Download Full-text

Intestinal CD14+ Macrophages Protect CD4+ T Cells From Activation-induced Cell Death via Exosomal Membrane TNF in Crohn’s Disease

Journal of Crohn s and Colitis ◽

10.1093/ecco-jcc/jjaa083 ◽

2020 ◽

Vol 14 (11) ◽

pp. 1619-1631 ◽

Cited By ~ 2

Author(s):

Huashan Liu ◽

Zhenxing Liang ◽

Fengwei Wang ◽

Xiaobin Zheng ◽

Ziwei Zeng ◽

...

Keyword(s):

T Cells ◽

Cell Death ◽

Crohn’S Disease ◽

T Cell ◽

Crohn's Disease ◽

Cd4 T Cells ◽

Ex Vivo ◽

Cd4 T Cell ◽

Activation Induced Cell Death ◽

Sustained Activation

Abstract Background and aims Sustained activation of CD4+ T cells plays important roles in the pathogenesis of Crohn’s disease [CD]. Under physiologic conditions, activated T cells can be timely eliminated by a process termed activation-induced cell death [AICD], restraining T cell over-activation and preventing immunological destruction. We inquired whether defective AICD might explain CD4+ T cell over-activation in CD and investigated the underlying mechanisms. Methods CD14+ macrophages [Mφ] and CD4+ T cells were isolated from intestinal tissues or peripheral blood of controls and CD patients. An ex vivo evaluation system was employed to simulate AICD and cell apoptosis was measured by flow cytometry. Results CD4+ T cells from CD patients fail to undergo AICD in the ex vivo system. Specifically, proinflammatory type 1 helper T [Th1] and type 17 helper T [Th17] cells, rather than immunosuppressive regulatory T [Treg] cells evade AICD in CD. CD14+ Mφ in the intestinal inflammatory microenvironment of CD promote AICD resistance in CD4+ T cells via a cell-to-cell contact-independent manner. Mechanistically, CD14+ Mφ released exosomes express membrane tumour necrosis factor [TNF] which engages TNFR2 on CD4+ T cells and triggers NF-κB signalling, thereby causing AICD resistance. Importantly, clinically applicable anti-TNF antibodies effectively blocked exosomal membrane TNF-induced CD4+ T cell AICD resistance. Conclusions CD14+ Mφ participate in CD pathogenesis by inducing AICD resistance through release of exosomal membrane TNF to activate the TNFR2/NF-κB pathway in CD4+ T cells. These results present new insights into CD pathogenesis and extend mechanistic understanding of anti-TNF agents. Proposed model CD14+ Mφ in the intestinal microenvironment of CD patients maintain the sustained activation of CD4+ T cells through exosomal membrane TNF to induce apoptosis resistance via TNFR2/NF-κB signalling, which could be effectively blocked by clinically applicable anti-TNF agents.

Download Full-text