Activation-driven T cell death. I. Requirements for de novo transcription and translation and association with genome fragmentation.

Ucker, David S.; Ashwell, Jonathan D.; Nickas, Gigi

doi:10.4049/jimmunol.143.11.3461

Cited by 171 publications

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“…Activation-driven cell death can be dissociated from lymphokine production. Stimulation of T-cell hybridomas via the TCR normally results in at least three distinct responsesthe production of IL-2, cell cycle arrest in the G1/Go compartment, and the induction of cell death-with indistinguishable antigen dose sensitivities (1,20,33). In the absence of the TCR, however, these responses are clearly dissociated.…”

Section: Resultsmentioning

confidence: 99%

“…where W, is the total number of wells plated, Wp is the observed number of wells with colonies, and N is the number of cells plated per well (33).…”

Section: Methodsmentioning

confidence: 99%

“…The monoclonal antibodies employed in this study were G7 (10) and 30H12 (16), both specific for murine Thy-1 and, respectively, mitogenic and nonmitogenic in soluble form; 8G12.1, specific for the Ly6A.2 antigen (2); and 145-2C11, specific for the murine CD3-r molecule (17). Antibodies were purified as previously described (33).…”

Section: Methodsmentioning

confidence: 99%

“…Stimuli that are normally mitogenic for T cells can induce cell death in transformed T-cell hybridomas (1,20,21,23,26,33) and in untransformed T cells (19,30,34). This process, activation-driven cell death, can be triggered by the presentation of appropriate antigen as well as by treatment with lectins and antibodies specific for the T-cell receptor complex (TCR) or other activation structures on the T-cell surface, such as Thy-1 and Ly-6 (20,21,33). The response is a cell-autonomous process of physiological cell death (32), dependent on macromolecular synthesis and associated with a characteristic nuclear disintegration and digestion of the dying cell's genome.…”

mentioning

confidence: 99%

“…The response is a cell-autonomous process of physiological cell death (32), dependent on macromolecular synthesis and associated with a characteristic nuclear disintegration and digestion of the dying cell's genome. We have argued that the process of activation-driven cell death likely represents the mechanism of negative selection and clonal deletion of T cells since it shares a number of properties with the in vivo process, especially the ability to be triggered in an antigen-specific manner, the cell-autonomous nature of the response, and its sensitivity to the immunosuppressive drug cyclosporin A (32)(33)(34).…”

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confidence: 99%

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Susceptibility to Cell Death Is a Dominant Phenotype: Triggering of Activation-Driven T-Cell Death Independent of the T-Cell Antigen Receptor Complex

Nickas

Meyers

Hebshi

et al. 1992

Molecular and Cellular Biology

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The failure of Thy-1 and Ly-6 to trigger interleukin-2 production in the absence of surface T-cell antigen receptor complex (TCR) expression has been interpreted to suggest that functional signalling via these phosphatidylinositol-linked alternative activation molecules is dependent on the TCR. We find, in contrast, that stimulation of T cells via Thy-1 or Ly-6 in the absence of TCR expression does trigger a biological response, the cell suicide process of activation-driven cell death. Activation-driven cell death is a process of physiological cell death that likely represents the mechanism of negative selection of T cells. The absence of the TCR further reveals that signalling leading to activation-driven cell death and to lymphokine production are distinct and dissociable. In turn, the ability of alternative activation molecules to function in the absence of the TCR raises another issue: why immature T cells, thymomas, and hybrids fail to undergo activation-driven cell death in response to stimulation via Thy-1 and Ly-6. One possibility is that these activation molecules on immature T cells are defective. Alternatively, susceptibility to activation-driven cell death may be developmentally regulated by TCR-independent factors. We have explored these possibilities with somatic cell hybrids between mature and immature T cells, in which Thy-1 and Ly-6 are contributed exclusively by the immature partner. The hybrid cells exhibit sensitivity to activation-driven cell death triggered via Thy-1 and Ly-6. Thus, the Thy-1 and Ly-6 molecules of the immature T cells can function in a permissive environment. Moreover, with regard to susceptibility to Thy-1 and Ly-6 molecules of the immature T cells can function in a permissive environment. Moreover, with regard to susceptibility to Thy-1 and Ly-6 triggering, the mature phenotype of sensitivity to cell death is genetically dominant.

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Section: Resultsmentioning

confidence: 99%

“…where W, is the total number of wells plated, Wp is the observed number of wells with colonies, and N is the number of cells plated per well (33).…”

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Susceptibility to Cell Death Is a Dominant Phenotype: Triggering of Activation-Driven T-Cell Death Independent of the T-Cell Antigen Receptor Complex

Nickas

Meyers

Hebshi

et al. 1992

Molecular and Cellular Biology

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Thy-1-Mediated phosphatidylinositol turnover in cultured rat glomerular mesangial cell

et al. 1996

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Thy-1 glycoprotein is expressed in rat glomerular mesangial cells, and anti-Thy-1 nephritis induced by anti-Thy-1 antibodies is a model of human renal diseases. In this study, we examined Thy-1-mediated biological reactions in cultured rat glomerular mesangial cells utilizing two anti-Thy-1 monoclonal antibodies (mAbs), 1-22-3 and OX-7. Incubation of the cells with these mAbs resulted in increased inositol trisphosphate (IP3) levels. The rise in IP3 produced by mAb 1-22-3 was greater than that produced by mAb OX-7 at the same dose. Incubation of mesangial cells with these mAbs resulted in an increase in the intracellular free calcium concentration ([Ca2+]i). mAb 1-22-3 induced a sustained increase in [Ca2+]i, while that induced by mAb OX-7 lasted 1-2 min, then decreased to the basal level. An transient increase in [Ca2+]i was also observed in Ca(2+)-free medium, indicating that these [Ca2+]i increases are due to release of Ca2+ from internal stores by IP3 without calcium flux across cell membrane. When cells were pretreated with protein tyrosine kinase (PTK) inhibitors (herbimycin A or genistein), Thy-1-mediated increases in [Ca2+]i were inhibited. These data suggest that Thy-1 induces the production of IP3 (including inositol 1,4,5-triphosphate, an intracellular Ca(2+)-releasing factor) and that PTKs may contribute to the Thy-1-mediated elevation of [Ca2+]i which presumably results from phospholipase C activation following Thy-1-mediated signaling in rat mesangial cells.

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Activation of T cells by superantigen: cytokine production but not apoptosis depends on MEK-1 activity

1998

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Engagement of the TCR may result in proliferation and cytokine release or programmed cell death. These two outcomes may be the consequence of distinct T cell receptor-coupled signal transduction pathways or may reflect quantitative differences in signaling strength via a single pathway. Here we show that genetic inhibition of MAP kinase kinase (MEK) by a dominant negative mutant or through chemical inhibition by PD98059 inhibits IL-2 secretion but not programmed cell death after TCR ligation by superantigen. This supports the hypothesis that T cell cytokine release and apoptosis result from signaling through distinct pathways and implies that the molecular signaling mechanisms regulating apoptosis of mature T cells and negative selection of thymocytes may be similar.

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Activation-driven T cell death. I. Requirements for de novo transcription and translation and association with genome fragmentation.

Cited by 171 publications

References 0 publications

Susceptibility to Cell Death Is a Dominant Phenotype: Triggering of Activation-Driven T-Cell Death Independent of the T-Cell Antigen Receptor Complex

Susceptibility to Cell Death Is a Dominant Phenotype: Triggering of Activation-Driven T-Cell Death Independent of the T-Cell Antigen Receptor Complex

Thy-1-Mediated phosphatidylinositol turnover in cultured rat glomerular mesangial cell

Activation of T cells by superantigen: cytokine production but not apoptosis depends on MEK-1 activity

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