The Role of c-FLIP in Modulation of CD95-induced Apoptosis

Scaffidi, Carsten; Schmitz, Ingo; Krammer, Peter H.; Peter, Marcus E.

doi:10.1074/jbc.274.3.1541

Cited by 750 publications

(766 citation statements)

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“…Thus, CD95-mediated apoptosis in type II cells can be inhibited by increased expression of anti-apoptotic Bcl-2 family members. Using the in vitro culture model of primary human T cells described in this study, we have shown here and in previous studies that primary human T cells can switch from one CD95 signaling type to the other and back [14,15]: Freshly activated T cells are CD95 type II cells and resistant towards CD95-mediated apoptosis (and AICD) through inhibition of the mitochondrial amplification loop. Short-term cultured activated T cells representing cells in the downphase of an immune response switch to CD95 type I cells and, thus, lose their dependence on mitochondria upon induction, of apoptosis.…”

Section: Discussionmentioning

confidence: 50%

“…4B). We have previously shown that freshly activated T cells (day 1) display very little DISC and, thus, resemble CD95 type II cells, whereas shortterm cultured day 6 cells display strong DISC formation and, thus, resemble CD95 type I cells [15]. Interestingly, like freshly activated, CD95-resistant day 1 T cells, LTC show very little DISC formation, suggesting that these cells are likewise CD95 type II cells (Fig.…”

Section: Reduced Disc Activity Of Ltc After Cd95 Stimulationmentioning

confidence: 75%

“…5B), suggesting that the strong DISC activity in day 6 cells, but not the low DISC activity in LTC, is sufficient to overcome this protection by high expression of anti-apoptotic Bcl-2 family members in day 6 cells. c-FLIP is a potent inhibitor of CD95-mediated apoptosis, which acts at the DISC level [15,34,36] through inhibition of caspase-8 activation [37]. Increased expression predominantly of the short splice variant of c-FLIP, c-FLIP S , has been suggested to contribute partially to CD95 resistance of freshly activated day 1 T cells, upon costimulation and upon restimulation of day 6 T cells [38][39][40].…”

Section: Reduced Mitochondrial Depolarization In Ltc After Cd95 Triggmentioning

confidence: 99%

“…The anticaspase-8 mAb C15 (mouse IgG2b) and the anti-c-FLIP mAb (NF-6) were described previously [15,44]. The HRPOconjugated goat anti-rabbit IgG was from Santa Cruz Biotechnology.…”

Section: Antibodiesmentioning

confidence: 99%

“…In contrast, activated T cells become CD95 sensitive after culture for approximately 6 days, thus mimicking T cells at the downphase of the immune response, and can be characterized as CD95 type I cells [15]. Immune reactions usually lead to immunological memory in form of persisting memory cells.…”

Section: Introductionmentioning

confidence: 99%

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In vitro generated human memory‐like T cells are CD95 type II cells and resistant towards CD95‐mediated apoptosis

et al. 2006

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An adaptive immune response implies expansion of activated T cells and subsequent elimination to maintain homeostasis in a process called activation-induced cell death. Some cells, however, differentiate into memory cells and ensure a strong secondary immune response. To analyze the apoptosis phenotype of memory T cells on a cellular and molecular level, we have established an in vitro model of T cell activation and generation of cells phenotypically and functionally similar to memory cells. These longterm cultured T cells show a CD95-resistant phenotype, although they are still sensitive towards TCR/CD3-mediated apoptosis. Biochemical analysis revealed that these cells shift from CD95 type I (direct signaling from the receptor) during the effector phase to CD95 type II cells (dependent on the mitochondrial amplification loop). Moreover, their mitochondria are protected, probably due to high expression levels of Bcl-x L and Bcl-2. Thus, our data suggest a mechanism how memory T cells acquire resistance towards bystander cell death via the CD95 system.

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Section: Discussionmentioning

confidence: 50%

Section: Reduced Disc Activity Of Ltc After Cd95 Stimulationmentioning

confidence: 75%

Section: Reduced Mitochondrial Depolarization In Ltc After Cd95 Triggmentioning

confidence: 99%

“…The anticaspase-8 mAb C15 (mouse IgG2b) and the anti-c-FLIP mAb (NF-6) were described previously [15,44]. The HRPOconjugated goat anti-rabbit IgG was from Santa Cruz Biotechnology.…”

Section: Antibodiesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

In vitro generated human memory‐like T cells are CD95 type II cells and resistant towards CD95‐mediated apoptosis

et al. 2006

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Caspase and calpain substrates: Roles in synaptic plasticity and cell death

1999

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Neurons are an unusual type of cell in that they send processes (axons and dendrites) over great distances. This elaborate morphology, together with their excitability, places neurons at risk for multiple insults. Recent studies have demonstrated that apoptotic and excitotoxic mechanisms not only contribute to neuronal death, but also to synaptic dysfunction and a breakdown in neural circuitry (see Mattson and Duan [1999] J. Neurosci. Res. 58:152-166, this issue). Proteases of the caspase and calpain families have been implicated in neurodegenerative processes, as their activation can be triggered by calcium influx and oxidative stress. Caspases and calpains are cysteine proteases that require proteolytic cleavage for activation. The substrates cleaved by caspases include cytoskeletal and associated proteins, kinases, members of the Bcl-2 family of apoptosis-related proteins, presenilins and amyloid precursor protein, and DNA-modulating enzymes. Calpain substrates include cytoskeletal and associated proteins, kinases and phosphatases, membrane receptors and transporters, and steroid receptors. Many of the substrates of caspases and calpains are localized in pre- and/or postsynaptic compartments of neurons. Emerging data suggest that, in addition to their roles in neurodegenerative processes, caspases and calpains play important roles in modulating synaptic plasticity. The present article provides a review of the properties of the different caspases and calpains, their roles in cell death pathways, and the substrates upon which they act. Emerging data are considered that suggest key roles for these proteases in the regulation of synaptic plasticity.

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