The process by which T cells are activated, and the consequences of activation (e.g. new gene transcription, cytokine production, apoptosis), are being investigated by a variety of approaches: 1) Inhibitors of proteasome activity block thymocyte apoptosis. We have found that IAPs (inhibitors of apoptosis) are selectively degraded in proteasomes in response to apoptotic stimuli. The IAPs themselves have ubiquitin protein ligase (E3) activity, and are responsible for their own ubiquitination. The dynamic regulation of E3 activity is currently the subject of investigation. 2) The TNF receptors are associated with two members of the IAP family (c-IAP1 and c-IAP2) as well as adaptor molecules such as TRAF2, which are necessary for signal transduction. We have found that upon TNF signaling TRAF2 is selectively ubiquitinated and degraded in proteasomes. How this is regulated in vivo, and the biological consequences thereof, is under investigation. 3) Glucocorticoids are immunosuppressive, largely because they interfere with the transcription of many activation-induced genes, a phenomenon that is thought to be due largely to direct binding of the liganded glucocorticoid receptor. We have found that a glucocorticoid-induced gene, GILZ, is able to attenuate TCR signaling events by directly binding to and interfering with the action of AP-1, providing an alternative mechanism for glucocorticoid-induced immunosuppression.
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