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) studies on the roles of src family kinases (especially Lck and Fyn) in T cell function. We have found activation of Lck leads to the rapid internalization of the T cell antigen receptor (TCR) and its destruction in lysosomes. Studies to determine the molecular mechanism for this phenomenon are ongoing. 2) the possible role of phosphatidylinositol-3 kinase (PI-3 kinase) in transducing activating signals via the T cell antigen receptor (TCR). Using both pharmacologic inhibitors of PI-3 kinase activity and dominant negative forms of the PI-3 kinase p85 subunit, we have demonstrated a critical role for this enzyme in IL-2 production. 3) 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, and are in the process of characterizing the transcription factor(s) that bind this regulatory element. 4) we have found that corticosteroids prevent activation-induced apoptosis, and have hypothesized that this phenomenon regulates antigen-specific selection of thymocytes. 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 improved. These results demonstrate that glucocorticoids, most likely those produced in the thymus itself, do in fact regulate positive selection of thymocytes.
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