Perhaps few questions in development have been so intractable as the means by which different cell fates are produced in response to a gradient of signals. These analogue-to-digital switches underlie the determination of cell fates in many organisms. T Lymphocyte development may be one of the best systems to understand this general problem because the critical signals are given at a stage where biochemical, genetic and cell biologic methods can all be brought to play. In lymphocytes, weak or transient signals are thought to produce positive selection (differentiation and proliferation) of T cells capable of reacting to self-MHC on thymic stromal cells. On the other hand, strong signals produced by self-antigen lead to death of cells responding to self-antigen. The pro-apoptotic protein Bim is required for negative selection but is not necessary for positive selection. Conversely, we have recently found that calcineurin is essential in T cells for positive selection, but dispensable for negative selection. Surprisingly calcineurin specifically controls the activation of ERK but not other MAP kinases or IkB, suggesting a revision of the accepted signaling pathways of thymocyte selection. These observations set the stage for a biochemical march from Bim and calcineurin to the molecule(s) that divert signals from positive to negative selection with increasing signal intensity. Current studies support several possible mechanisms by which signals of different intensity could control selection. To avoid the difficulties encountered with forward analysis of biochemical pathways we will work backward from Bim and calcineurin to define the biochemical pathways that control their activity in CD4+, CD8+ thymocytes. Our goal in these studies will be to define the lowest common mediator necessary for activation of both Bim and calcineurin and hence positive and negative selection. We will then determine the mechanism by which this molecule is induced to channel high intensity signals to Bim and low intensity signals to calcineurin. We will also define the processes downstream of calcineurin that mediate positive selection including the mechanism of NFATc nuclear import and export, the set of genes that are dependent on calcineurin activity in positive selection and how these genes give rise to a population of immunologically competent peripheral lymphocytes. Defining these mechanisms should lead to a more complete understanding of immune defense and provide useful information for development of new therapies. ? ?
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