Biochemical Mechanisms of IL-2–Regulated Fas-Mediated T Cell Apoptosis

Refaeli, Yosef; Parijs, Luk Van; London, Cheryl A.; Tschopp, Jürg; Abbas, Abul K.

doi:10.1016/s1074-7613(00)80566-x

Cited by 579 publications

(467 citation statements)

References 39 publications

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“…We also looked at the expression of FLIP, a cellular inhibitor of the Fas pathway. Refaeli et al have reported that FLIP is down-regulated at day 3 of activa- tion with anti-CD3 [4], whereas we induced perforindependent death after only 2 days of activation. Consistent with Refaeli's results, FLIP expression was induced in activated B6 T cells by day 1, remained high at day 3, and fell off by days 4 and 5 in our system (Fig.…”

Section: Early Activation-induced Cell Death Requires Perforincontrasting

confidence: 54%

“…The better known pathway is initiated by activation of caspase 8 via signaling through cell surface receptors such as Fas or TNFR [1][2][3]. Activation of the Fas signaling pathway requires down-regulation of the FLICE-like inhibitor protein (FLIP), an IL-2-dependent event that occurs about 3 days after T cell activation [4]. A second apparently independent pathway depends upon the presence of perforin, and can be demonstrated before day 3 following activation and in cells from FasLdeficient mice [5].…”

Section: Introductionmentioning

confidence: 99%

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Perforin‐dependent activation‐induced cell death acts through caspase 3 but not through caspases 8 or 9

et al. 2003

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Activation-induced cell death (AICD) is a phenomenon in which activated T cells undergo apoptosis upon restimulation. We are studying a form of AICD that can occur before cells become competent to die by Fas (hence "early" AICD) and which depends on the presence of perforin. Previous studies indicate that it does not occur through granule exocytosis but via some endogenous pathway. We here investigate a possible role for caspases. Caspase 3 -/-cells were protected, suggesting a role for caspase 3 in early AICD. After recrosslinking, caspase 3 activity could be detected in cell lysates between 3 and 12 h, and CD8 + T cells became annexin V-positive between 15 and 18 h. Blocking anti-Fas ligand antibody failed to inhibit death, and no processing of either caspase 8 or caspase 9 was detected in recrosslinked cells. Furthermore, T cells lacking functional caspase 9 continued to die in early AICD. Thus, perforin-dependent early AICD appears to require activation of caspase 3, but not caspases 8 or 9. As perforin has no intrinsic catalytic abilities, we propose that it releases some endogenous activity that can activate caspase 3.

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Section: Early Activation-induced Cell Death Requires Perforincontrasting

confidence: 54%

Section: Introductionmentioning

confidence: 99%

Perforin‐dependent activation‐induced cell death acts through caspase 3 but not through caspases 8 or 9

et al. 2003

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“…For example, IL-2 and IL-15 play vital roles in proliferation of T cells and augmentation of the cytolytic activity of NK cells . IL-2 also plays an important role in the elimination of autoreactive T cells (Lenardo, 1991;Refaeli et al, 1998;Van Parijs et al, 1997) and can promote immunoglobulin synthesis by B cells (Lin and Leonard, 1997). IL-15 appears to be essential for the development of NK cells, as well as proliferation of CD8 + memory T cells (Lodolce et al, 1998;Zhang et al, 1998b) and lymphocyte homing (Lodolce et al, 1998).…”

Section: An Overview Of Il-2 Family Cytokinesmentioning

confidence: 99%

“…This function is especially important for eliminating auto-reactive T cells in vivo and thus for terminating abnormal T cell responses and maintain tolerance. It has recently been demonstrated that activation of Stat5 proteins by IL-2 leads to an increased expression of Fas ligand (FasL) (Refaeli et al, 1998;Van Parijs et al, 1999). The evidence for the involvement of Stat5 proteins in promoting IL-2-induced AICD is provided recently (Van Parijs et al, 1999).…”

Section: Potential Roles Of Stat5 In Transformation Immune Surveillamentioning

confidence: 99%

The role of Stat5a and Stat5b in signaling by IL-2 family cytokines

2000

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“…Classical AICD of T cells is a process that eliminates previously activated T cells. In vitro, this process is Fas/FasL and IL-2 dependent [23]. Previously it was reported that Con A and IL-2-stimulated lymph node blast cells from WT and p53 À/À mice were equally sensitive to AICD [14,15].…”

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confidence: 99%

Defective T‐cell receptor‐induced apoptosis of T cells and rejection of transplanted immunogenic tumors in p53^−/− mice

2010

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Mice lacking the tumor suppressor gene p53 spontaneously develop T-cell lymphomas at a high rate, suggesting that in these mice lymphomas arise due to defective apoptosis mechanisms in T cells mediated by p53. However, a role of p53 in regulation of T-cell responses or apoptosis has been poorly defined. TCR-mediated signaling in the absence of CD28 costimulation induces both apoptosis and proliferation of naïve T cells from WT mice. In this report we show that, in response to TCR stimulation, T cells from naïve p53-deficient mice exhibited higher proliferation and drastically reduced apoptosis than WT T cells. CD28 costimulation enhanced the proliferation of TCR-stimulated WT and p53 À/À T cells, suggesting that p53 uncouples CD28-mediated antiapoptotic and proliferative signals. To evaluate the physiological significance of these findings, we transplanted OVA expressing-EG.7 tumor cells into WT and p53 À/À mice. Unlike WT mice, p53 À/À mice exhibited a robust tumor-resistant phenotype and developed cytotoxic T-cell responses against OVA. Collectively, these data support the hypothesis that p53 is an essential factor in negative regulation of T-cell responses and have implication for immunomodulation during treatment of cancers and other inflammatory conditions. Key words: p53 . T-cell apoptosis and immune responses Supporting Information available online IntroductionTransformation related protein 53 (Trp53 or p53) is a member of the p53 transcription factor family that regulates DNA repair, genomic integrity, DNA replication, cell proliferation and apoptosis [1][2][3]. It contains an N-terminal transactivation domain, a C-terminal tetramerization domain and a central DNA binding domain. Under normal conditions p53 is expressed at low levels in a variety of cell types. Exposure of cells to ionizing radiation, DNA damage, or certain cellular or physiological stresses leads to stabilization and activation of p53 and its pathway [2]. Once activated, p53 binds to target DNA and initiates transcription of target genes that directly or indirectly inhibit the cell cycle or induce cell death [4,5]. Lack of p53 expression or function is related to development of a vast variety of tumor types and a role for p53 in apoptosis of cells has been the subject of numerous studies for many years.Traditionally, increased expression p53 has been reported in conditions that favor tumoroigenesis, e.g. ionizing radiations. However, p53 expression is also upregulated during . This increased level of p53 in arthritic synovium joints can be seen in the early stages of disease development [7]. Further, lymphocytes from rheumatoid arthritis patients express lower levels of p53 mRNA and protein, and have an impaired ability to induce p53 expression after exposure to gamma radiation, which correlated with increased survival of CD4 1 and CD8 1 T cells after exposure to gamma radiation [8]. Mice lacking p53 also display increased susceptibility to experimentally induced autoimmune diseases. p53 À/À mice are more susceptible than WT mice to low...

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Biochemical Mechanisms of IL-2–Regulated Fas-Mediated T Cell Apoptosis

Cited by 579 publications

References 39 publications

Perforin‐dependent activation‐induced cell death acts through caspase 3 but not through caspases 8 or 9

Perforin‐dependent activation‐induced cell death acts through caspase 3 but not through caspases 8 or 9

The role of Stat5a and Stat5b in signaling by IL-2 family cytokines

Defective T‐cell receptor‐induced apoptosis of T cells and rejection of transplanted immunogenic tumors in p53^−/− mice

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Biochemical Mechanisms of IL-2–Regulated Fas-Mediated T Cell Apoptosis

Cited by 579 publications

References 39 publications

Perforin‐dependent activation‐induced cell death acts through caspase 3 but not through caspases 8 or 9

Perforin‐dependent activation‐induced cell death acts through caspase 3 but not through caspases 8 or 9

The role of Stat5a and Stat5b in signaling by IL-2 family cytokines

Defective T‐cell receptor‐induced apoptosis of T cells and rejection of transplanted immunogenic tumors in p53−/− mice

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Defective T‐cell receptor‐induced apoptosis of T cells and rejection of transplanted immunogenic tumors in p53^−/− mice