T cell development in the thymus progresses as an ordered series of developmental steps best characterized by variable expression of CD4 and CD8 coreceptors. Most thymocytes are immature and express both CD4 and CD8 coreceptors on their surface and are referred to as Double Positive (DP) cells. DP cells are the precursors of mature T cells which express only one coreceptor molecule and so are referred to as Single Positive (SP) cells. We have found that the differentiation of DP thymocytes into SP T cells requires 3 distinct signaling steps which we have termed induction, commitment, rescue. The induction step requires TCR signals to fix TCR specificity and to upregulate CD5 and CD69 expression. The commitment step requires TCR + coreceptor signaling to extinguish either CD4 or CD8 coreceptor expression, and the rescue step involves TCR-signaled upregulation of the anti- apoptotic protein bcl-2. Importantly, we have developed in vitro systems and in vivo adoptive transfer systems in which each of the 3 positive selection steps can be studied molecularly. For example we have found that coreceptor extinction proceeds in two discrete steps involving the coordinate activity of both post-transcriptional and transcriptional regulatory mechanisms to initially destabilize both CD4 and CD8 coreceptor RNAs and to then selectively terminate CD8 coreceptor transcription. With regard to the role of CD4 and CD8 coreceptors in thymic development, we have found that coreceptor signaling importantly influences the direction of positive selection in the thymus even when the MHC specificity of the TCR and coreceptor are mismatched. Indeed, we have studied coreceptor signaling in detail and have discovered that coreceptor molecules are not only associated with intracellular Lck molecules but are also associated with the adaptor molecule LAT, demonstrating that surface coreceptor molecules perform 2 functions in TCR signal transduction: first bringing Lck into the TCR complex and then bringing LAT into the TCR complex. We have especially focused on the CD8 coreceptor complex and found that the stoichiometry of CD8 surface complexes is not an ab dimer as generally thought, but rather is a trimer of two a chains linked to a b chain. In fact, an important role of the CD8b chains is to promote trimerization of the surface complex, enhancing the binding to extracellular MHC class I molecules and enhancing the association with intracellular signaling molecules. - immunology, receptor signaling, T-cell development, Thymus,
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