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cAMP analogs prevent activation-induced apoptosis of T cell hybridomas
1Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan, R.O.C.
Abstract:
Activation of T cell hybridomas through their TCR leads to secretion of IL-2, inhibition of proliferation, and apoptosis. The identification of various inhibitors that prevent activation-induced T cell death (AICD) has helped identify several essential events in apoptosis. For example, inhibition of AICD by dexamethasone indicates a connection between these two programmed death pathways. In this study, we have investigated the interaction between the cAMP signal transduction pathway and the activation- or glucocorticoid-induced cell death. cAMP induced DNA fragmentation in thymocytes. T cell hybridomas displayed different sensitivity to cAMP. Regardless of its cAMP sensitivity, programmed cell death promoted by anti-CD3 or Ag in hybridoma was prevented by the presence of cAMP analogs. In contrast, cAMP had no effect on glucocorticoid-induced T cell death. The inhibitory effect of cAMP on AICD was unlikely to be due to quenching of T cell activation signals, because cAMP added 1 h after T cell activation could still prevent cell death. In addition, the increased binding of AP-1, NF-AT, and NF-kappa B during T cell activation was not significantly affected by cAMP. The presence of the inhibitory cAMP-mediated signals, together with the glucocorticoid-induced pathway, suggest there are at least two distinct mechanisms regulating AICD in immature lymphocytes.
Insights
Cyclic AMP (cAMP) analogs prevent T cell death induced by activation but not by glucocorticoids. This suggests distinct pathways regulate programmed cell death in lymphocytes.
Area of Science:
- Immunology
- Cell Biology
- Molecular Biology
Background:
- T cell activation via the T cell receptor (TCR) triggers IL-2 secretion, proliferation inhibition, and apoptosis.
- Activation-induced cell death (AICD) is a critical process in lymphocyte homeostasis.
- Dexamethasone inhibition of AICD suggests a link between glucocorticoid and AICD pathways.
Purpose of the Study:
- To investigate the interplay between the cyclic AMP (cAMP) signal transduction pathway and activation- or glucocorticoid-induced T cell death.
- To determine if cAMP modulates T cell death pathways.
Main Methods:
- T cell hybridomas and thymocytes were used to study cell death.
- Cell death was induced by anti-CD3 antibody, antigen (Ag), or dexamethasone.
- The effect of cAMP analogs on programmed cell death was assessed.
- DNA fragmentation was measured.
- Transcription factor binding (AP-1, NF-AT, NF-kappa B) was analyzed.
Main Results:
- cAMP induced DNA fragmentation in thymocytes.
- T cell hybridomas showed varied sensitivity to cAMP.
- cAMP analogs prevented anti-CD3 or Ag-induced T cell death, irrespective of cAMP sensitivity.
- cAMP did not affect glucocorticoid-induced T cell death.
- cAMP's inhibitory effect on AICD was not due to quenching activation signals, as it inhibited cell death even when added 1 hour post-activation.
- cAMP did not significantly alter the binding of AP-1, NF-AT, and NF-kappa B during T cell activation.
Conclusions:
- cAMP-mediated signals inhibit AICD in T cells.
- Glucocorticoid-induced T cell death operates via a distinct pathway.
- At least two separate mechanisms regulate AICD in immature lymphocytes: one involving cAMP and another involving glucocorticoids.