Autocrine T-cell suicide mediated by APO-1/(Fas/CD95)

Dhein, Jens; Walczak, Henning; Bäumler, Caroline; Debatin, Klaus‐Michael; Krammer, Peter H.

doi:10.1038/373438a0

Cited by 1,549 publications

(1,061 citation statements)

References 24 publications

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“…Activation of T lymphocytes increases their expression of Fas and induces their expression of Fas-L within 24 h, and they become susceptible to Fasmediated apoptosis 3-4 days after activation (Brunner et al, 1995, Ju et al, 1995and Dhein et al, 1995. The ligation of Fas on the surface of the T cell can be mediated by Fas-L on the same T cell or by Fas-L expressed by other cells (Brunner et al, 1995 andDhein et al, 1995). Using four-colour flow cytometry on lymphocytes extracted from GBM, we have shown that T cells expressing Fas-L are 8 times more likely to undergo apoptosis than those not expressing Fas-L.…”

Section: Discussionmentioning

confidence: 99%

T-cell apoptosis in human glioblastoma multiforme: Implications for immunotherapy

Walker

Chuah

Rist

et al. 2006

Journal of Neuroimmunology

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We used immunohistochemistry and flow cytometry to assess apoptosis in human glioblastoma multiforme (GBM). Our immunohistochemical study revealed apoptosis of glioma cells expressing glial fibrillary acidic protein and of CD3 + T cells infiltrating GBM. To quantify and phenotype the apoptotic T cells, we performed flow cytometry on lymphocytes separated from GBM. The cells were stained with annexin-V-FLUOS/propidium iodide to identify apoptosis. We found that high proportions of both the CD4 + and CD8 + T cells were apoptotic. In particular, we found that T cells expressing Fas ligand (Fas-L, CD95L) were eight times more vulnerable to apoptosis than those not expressing Fas-L, which suggests that the Tcell apoptosis is induced by overactivation of the T-cell receptor, possibly in the absence of appropriate costimulation. Our results have implications for the design of immunotherapies for GBM.

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Section: Discussionmentioning

confidence: 99%

T-cell apoptosis in human glioblastoma multiforme: Implications for immunotherapy

Walker

Chuah

Rist

et al. 2006

Journal of Neuroimmunology

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“…While most receptors of this family are implicated in proliferative processes, TNF receptor and Fas, when cross-linked by antibodies or their physiological ligands (TNF or the Fas ligand, respectively), frequently induce apoptosis [2][3][4][5]. TNF has a main role in inflammatory responses [4] while Fas-mediated apoptosis participates in the effector function of cytotoxic T-lymphocytes [6,"], as well as in the auto-elimination of activated mature T-~ells, and hence, in peripheral tolerance [5,8,9].…”

Section: Introductionmentioning

confidence: 99%

mtDNA‐depleted U937 cells are sensitive to TNF and Fas‐mediated cytototxicity

et al. 1995

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It has been proposed that TNF cytotoxicity is mediated by reactive oxygen intermediates generated by uncoupling of mitochondrial respiration. We have compared sensitive U937 cells and derived cell lines depleted of mtDNA for their ability to undergo TNF-and Fas-induced apoptosis. Cells lacking around 98% of mtDNA were still sensitive to TNF-induced apoptosis. U937 cells devoid of mtDNA (U937-p °) were resistant to TNF, but this was due to the loss of its 55 kDa receptor. U937-p ° cells were also resistant to docosahexaenoic acid, which causes U937 cell death by lipid peroxidation. These cells were sensitive to anti-Fas toxicity. The results indicate that TNF and Fasinduced toxicity occurs by a mechanism mostly independent of mitochondrial free radical generation.The mechanism by which Fas ligation triggers apoptosis, as well as a general biochemical mechanism for the apoptosis process itself, are unknown [5]. Some reports have suggested, however, the lack of implication of oxidative damage in cytotoxicity induced with anti-Fas, using antioxidants [14,15] or anaerobic conditions [16].In the present work, we have studied the effect of TNF and anti-Fas on U937 cells and in derived cell lines depleted of mtDNA by prolonged exposure to low doses of ethidium bromide. Results indicate that impairment of mitochondrial function and lipid peroxidation do not play a key role in the apoptosis induced by both molecules in human myeloid cells.

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“…This results in shedding of the receptor-binding FasL ectodomain (referred to as soluble Fas ligand (sFasL)), the biological role of which is still disputed (reviewed in 1 ). sFasL can either cause apoptosis at a distant site 6,7 or alternatively dampen the apoptotic response by blocking Fas receptors. 8,9 The fate of the remaining membrane-anchored N-terminal portion of FasL, which comprises a transmembrane region and the proline-rich FasL intracellular domain (FasL ICD), has not been studied so far.…”

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confidence: 99%

The Fas ligand intracellular domain is released by ADAM10 and SPPL2a cleavage in T-cells

Cahuzac²,

et al. 2007

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Fas ligand (FasL) is a type II transmembrane protein belonging to the tumor necrosis factor family. Its binding to the cognate Fas receptor triggers the apoptosis that plays a pivotal role in the maintenance of immune system homeostasis. The cell deathinducing property of FasL has been associated with its extracellular domain, which can be cleaved off by metalloprotease activity to produce soluble FasL. The fate of the remaining membrane-anchored N-terminal part of the FasL molecule has not been determined. Here we show that post-translational processing of overexpressed and endogenous FasL in T-cells by the disintegrin and metalloprotease ADAM10 generates a 17-kDa N-terminal fragment, which lacks the receptor-binding extracellular domain. This FasL remnant is membrane anchored and further processed by SPPL2a, a member of the signal peptide peptidaselike family of intramembrane-cleaving proteases. SPPL2a cleavage liberates a smaller and highly unstable fragment mainly containing the intracellular FasL domain (FasL ICD). We show that this fragment translocates to the nucleus and is capable of inhibiting gene transcription. With ADAM10 and SPPL2a we have identified two proteases implicated in FasL processing and release of the FasL ICD, which has been shown to be important for retrograde FasL signaling.

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Autocrine T-cell suicide mediated by APO-1/(Fas/CD95)

Cited by 1,549 publications

References 24 publications

T-cell apoptosis in human glioblastoma multiforme: Implications for immunotherapy

T-cell apoptosis in human glioblastoma multiforme: Implications for immunotherapy

mtDNA‐depleted U937 cells are sensitive to TNF and Fas‐mediated cytototxicity

The Fas ligand intracellular domain is released by ADAM10 and SPPL2a cleavage in T-cells

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