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Activation-induced Cell Death (activation-induced + cell_death)

Distribution by Scientific Domains

Medical Sciences	100%

Selected Abstracts

,Activation-induced cell death': a special program able to preserve the homeostasis of the skin?

EXPERIMENTAL DERMATOLOGY, Issue 1 2002
Giuseppe De Panfilis
Abstract: The ,activation-induced cell death' (AICD) is a molecular system leading to death of antigen-activated T lymphocytes, in order to avoid accumulation of harmful cytokine-releasing cells. This article reviews both the molecular mechanisms working in AICD and the role played by such mechanisms in preventing a number of skin diseases. Specifically, because AICD removes activated and autoreactive T cells through a CD95-/CD95-L-mediated suicide, skin diseases were scrutinized in which such valuable machinery could be lacking. Indeed, at least some inflammatory skin diseases, including psoriasis and atopic dermatitis, can be sustained by an increased survival of activated T lymphocytes associated with deficient CD95-/CD95-L-mediated AICD of such strong pro-inflammatory cells. In addition, autoreactive skin diseases, including, e.g. alopecia areata, lichen planus and other lichenoid tissue reactions, can be related to autoreactive T lymphocytes which could be unable to undergo CD95-/CD95-L-mediated AICD. Finally, a lack of AICD may be executive even in favoring cutaneous T cell lymphoma. Thus, because inflammatory, autoreactive and neoplastic skin diseases can be associated with a deficient CD95-/CD95-L-mediated suicide of activated T cells, AICD is likely to represent a fundamental program to preserve the homeostasis of the skin. Therapeutic approaches able to restore the AICD machinery promise to successfully treat such relevant skin diseases. [source]

Collagen type,I signaling reduces the expression and the function of human receptor activator of nuclear factor -,B ligand (RANKL) in T,lymphocytes

EUROPEAN JOURNAL OF IMMUNOLOGY, Issue 12 2005
Steve Gendron
Abstract The mechanisms by which ,1 integrins modulate T,cell functions are still poorly defined. We have previously reported that signaling via the collagen type,I (Coll,I) receptor, ,2,1 integrin, inhibited FasL expression and protected Jurkat T,cells from activation-induced cell death (AICD). In this study, we examined whether Coll,I signaling in T,cells also modulates the expression of the human receptor activator of nuclear factor-,B ligand (RANKL), a recently identified TNF family member which has important functions in osteoclastogenesis, cell survival and apoptosis. Our results show that in both Jurkat T,cells and human primary T,cells, Coll,I signaling significantly reduces activation-induced RANKL expression by 50,60%. We also found that RANKL is not involved in AICD but participates in doxorubicin-induced apoptosis of leukemia T,cell lines including Jurkat, CEM and HSB-2. In this respect, Coll,I protected leukemia T,cell lines from doxorubicin-induced apoptosis by inhibiting doxorubicin-induced RANKL expression. Together, our results suggest that by limiting the production of RANKL, Coll,I signaling may contribute to the resistance of leukemia T,cells to chemotherapy. Our study also emphasizes the importance Coll,I signaling may have in the control of RANKL-associated T,cell functions. [source]

The ratio between dendritic cells and T,cells determines the outcome of their encounter: Proliferation versus deletion

EUROPEAN JOURNAL OF IMMUNOLOGY, Issue 10 2005

Abstract Dendritic cells (DC) either induce T,cell tolerance or contribute to the initiation and modulation of T and B,cell responses. Since many of the variables determining the thresholds of naive T,cell priming were defined in vitro using a homogeneously matured DC population, we here focused on partially mature DC which might reflect the occurrence of tumor-infiltrating and thymic DC. To predict how those DC regulate the induction of antigen-specific T,cell proliferation and T,cell tolerance, we co-cultured ovalbumin-pulsed murine DC at different ratios with antigen-specific DO11.10 transgenic T,cells. Whereas partially mature DC at a DC/T,cell ratio of 1,:,10 supported proliferation, a DC/T,cell ratio of 1,:,2 induced proliferation arrest in naive CD4+ T,cells. The acquisition of the NK cell inhibitory markers NK1.1 and KLRG on T,cells exposed to high numbers of DC suggests a role for these molecules in the protection of antigen-responsive T,cells from exhaustion by overstimulation. Mechanistically, abortive T,cell proliferation upon encounter of high numbers of partially mature DC is caused by an apoptosis-related pathway, suggesting that excessive antigen density without sufficient costimulation results in activation-induced cell death. [source]

The Bcl-2 family pro-apoptotic molecule, BNIP3 regulates activation-induced cell death of effector cytotoxic T lymphocytes

IMMUNOLOGY, Issue 1 2003
J. Wan
Summary BNIP3 is a recently described pro-apoptotic member of the Bcl-2 family and in BNIP3 cDNA-transfected cell lines, cell death occurs via a caspase-independent pathway with opening of the mitochondrial permeability transition (PT) pore and rapid loss of mitochondrial transmembrane potential (,,m). However, its expression or function in physiologic cell types is not known. Our results using the T-cell receptor transgenic mice P14, specific for lymphocyte choreomeningitis virus (LCMV) glycoprotein, show that in contrast to the other Bcl-2 family pro-apoptotic molecules, BNIP3 is transcriptionally highly up-regulated in effector cytotoxic T lymphocytes (CTL). Because CTL have a propensity to undergo activation-induced cell death (AICD) upon restimulation, we tested for other features associated with BNIP3-induced cell death. AICD of CTL was caspase-independent as determined by measuring caspase activation during target cell killing as well as by lack of inhibition with caspase inhibitors. Moreover, similar to BNIP3-induced cell death, CTL apoptosis was associated with increased production of reactive oxygen species and decreased ,,m. Finally, retroviral transduction of BNIP3 antisense RNA diminished AICD in effector CTL. These results suggest that BNIP3 may play an important role in T-cell homeostasis by regulating effector CTL numbers. [source]

Selective elimination of hepatic natural killer T cells with Concanavalin A improves liver regeneration in mice

LIVER INTERNATIONAL, Issue 3 2006
Wen Huang
Abstract: Background: Although concanavalin A (Con A) as a T cell stimulant can cause natural killer T (NKT) cell-mediated liver injury in mice and a nonhepatotoxic dose of Con A can trigger innate immune cells including NKT cells to prevent tumor metastasis in the liver, little is known about the role of Con A-primed NKT cells in liver repair. In this study, we aimed to investigate the effect of pretreatment with a nontoxic dose of Con A on subsequent liver regeneration in mice. Methods: A nontoxic dose of Con A was injected intravenously 24 h before partial hepatectomy (PHx), which was used as a model of liver regeneration. Ratios of remnant liver mass to body weight, bromodeoxyuridine (BrdU) incorporation and proliferating cell nuclear antigen (PCNA) labeling were used to assess liver regeneration. Results: Hepatic mononuclear cells were isolated and analyzed by flow cytometry. After PHx, the ratios of liver weight to body weight, PCNA-positive hepatocytes and BrdU-positive hepatocytes in Con A-pretreated mice were significantly higher than that of phosphate-buffered saline-treated mice, indicating that Con A pretreatment can accelerate liver regeneration. Flow cytometric analysis showed that NKT cells were significantly activated and selectively eliminated after the Con A administration. Moreover, NKT cells expressed more apoptosis-related molecules, Fas and Annexin V. Conclusions: Taken together, Con A accelerates liver regeneration in mice by eliminating hepatic NKT cells via activation-induced cell death. [source]

Generation of NO by Bystander Human CD8 T Cells Augments Allogeneic Responses by Inhibiting Cytokine Deprivation-Induced Cell Death

AMERICAN JOURNAL OF TRANSPLANTATION, Issue 10 2009
J. C. Choy
Nitric oxide (NO), generated by inducible NO synthase (iNOS) in bystander human CD8 T cells, augments the accumulation of allogeneically activated human CD8 T cells in vitro and in vivo. Here, we report that iNOS-derived NO does not affect T-cell proliferation but rather inhibits cell death of activated human CD8 T cells after activation by allogeneic endothelial cells in culture. Exogenous NO did not affect activation-induced cell death of human CD8 T cells but specifically reduced death of activated T cells due to cytokine deprivation. NO-mediated inhibition of T-cell death did not involve cGMP signaling, and NO did not affect the expression of Bcl-2-related proteins known to regulate cytokine deprivation-induced cell death. However, NO inhibited the activity of caspases activated as a consequence of cytokine deprivation in activated T cells. This protective effect correlated with S-nitrosylation of caspases and was phenocopied by z-VAD.fmk and z-LEHD.fmk, pharmacological inhibitors of caspases. In summary, our findings indicate that NO augments the accumulation of activated human T cells principally by inhibiting cytokine deprivation-induced cell death through S-nitrosylation of caspases. [source]

Impaired activation-induced cell death promotes spontaneous arthritis in antigen (cartilage proteoglycan),specific T cell receptor,transgenic mice

ARTHRITIS & RHEUMATISM, Issue 10 2010
Ferenc Boldizsar
Objective To investigate whether genetic preponderance of a T cell receptor (TCR) recognizing an arthritogenic peptide of human cartilage proteoglycan (PG) is sufficient for development of arthritis. Methods We performed a longitudinal study using BALB/c mice expressing a TCR that recognizes the arthritogenic ATEGRVRVNSAYQDK peptide of human cartilage PG. PG-specific TCR,transgenic (PG-TCR,Tg) mice were inspected weekly for peripheral arthritis until 12 months of age. Peripheral joints were examined histologically, and T cell responses, T cell activation markers, serum cytokines, and autoantibodies were measured. Apoptosis and signaling studies were performed in vitro on T cells from aged PG-TCR,Tg mice. Results Spontaneous arthritis developed as early as 5,6 months of age, and the incidence increased to 40,50% by 12 months of age. Progressive inflammation began with cartilage and bone erosions in the interphalangeal joints, and later expanded to the proximal joints of the front and hind paws. Spontaneous arthritis was associated with a high proportion of activated CD4+ T cells, enhanced interferon-, and interleukin-17 (IL-17) production, and elevated levels of serum autoantibodies. PG-TCR,Tg mice lacking IL-4 developed arthritis earlier and at a higher incidence than IL-4,sufficient mice. Antigen-specific activation,induced cell death was diminished in vitro in CD4+ T cells of PG-TCR,Tg mice with spontaneous arthritis, especially in those lacking IL-4. Conclusion The presence of CD4+ T cells expressing a TCR specific for an arthritogenic PG epitope is sufficient to trigger spontaneous autoimmune inflammation in the joints of BALB/c mice. IL-4 appears to be a negative regulator of this disease, through attenuation of activation-induced cell death. [source]

CTLA-4 (CD152) controls homeostasis and suppressive capacity of regulatory T cells in mice

ARTHRITIS & RHEUMATISM, Issue 1 2009
Paula Kolar
Objective CD4+CD25+ regulatory T cells (known as Treg cells) suppress unwanted and autoreactive T cell responses. Treg cells express the costimulatory molecule CTLA-4 intracellularly, but the mechanisms by which Treg cells exploit CTLA-4 signaling remain unclear. The present study was undertaken to investigate the role of CTLA-4 in controlling the homeostasis and suppressive function of Treg cells. Methods Murine Treg cells were analyzed by flow cytometry for coexpression of CTLA-4 and typical Treg cell,expressed molecules, and the influence of CTLA-4 on T cell proliferation, suppression, and apoptosis was investigated by in vitro assays. To analyze the importance of CTLA-4 in Treg cell,mediated suppression in vivo, wild-type Treg cells were transferred into CTLA-4,deficient mice displaying lymphoproliferation, and survival was monitored over time. Results A strong correlation between expression of forkhead box P3 and ex vivo expression of CTLA-4 in Treg cells was observed. Inhibition of CTLA-4 signaling in Treg cells during in vitro stimulation increased cell cycling and led to enhanced activation-induced cell death (AICD), which was mediated by CD95/CD95 ligand,induced activation of caspases. Blockade of CTLA-4 signaling resulted in impairment of the suppressive capacity of Treg cells. Despite these effects, high amounts of Treg cells persisted in CTLA-4,deficient mice. Results of transfer experiments in CTLA-4,deficient mice showed that the mice had a significantly prolonged lifespan when CTLA-4,competent Treg cells were injected. Conclusion Expression of CTLA-4 on Treg cells serves to control T cell proliferation, to confer resistance against AICD, and to maintain the suppressive function of Treg cells. [source]