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) activation-induced apoptosis of T cell hybridomas is mediated by upregulation of the ligand for Fas (FasL). We have identified a single major site 5 of the transcription initiation site that is required for initiation of fasL transcription. This site is bound by the Egr family of transcription factors, and Egr-2 and Egr-3 (but not Egr-1) are responsible for transactivation of gene transcription at this site. 2) We have found that corticosteroids prevent activation-induced apoptosis, and have hypothesized that this phenomenon regulates antigen-specific thymocyte selection. We have crossed transgenic mice that express antisense glucocorticoid receptor in immature thymocytes with lpr autoimmune mice, and have found that TCR Vbeta usage is altered and autoimmunity and lymphadenopathy are greatly diminished. Moreover, B10.BR (H-2k) mice bearing this antisense transgene no longer respond to the antigen pigeon cytochrome c, although they respond normally to more complex antigens such as PPD and alloantigen. These results demonstrate that glucocorticoids, likely those produced in the thymus itself, do in fact regulate positive and negative selection by antagonizing TCR-mediated signals, and therefore shape the peripheral immune repertoire. Studies on the possible role of glucocorticoids in the generation of autoimmunity are ongoing. 3) 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 mechanism by which this occurs, and the role of ubiquitination, are being investigated. 4) Glucocorticoids are immunosuppressive, largely because they interfere with the transcription of many activation-induced genes. They are also potent inducers of apoptosis in thymocytes. We are currently use DNA chip technology to look for glucocorticoid-induced genes that participate in these activities. - Apoptosis, Cell Cycle, Fas, Signal Transduction, Thymocyte selection, Glucocorticoids, - Neither Human Subjects nor Human Tissues
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