Description): New T cells are extensively generated in the thymus, mainly from fetal to young age. Immature T cells (thymocytes) that subtly interact with self MHC/peptide complexes are positively selected by thymic epithelial cells. Furthermore, thymocytes that express T cell receptors (TCRs) that interact too strongly with self MHC/peptide complexes are negatively selected by thymic dendritic cells and macrophages. The role of self derived peptides in the process of selection of T cells is indisputable. However, the mechanism of how different self MHC/peptide complexes select immature T cells remains unclear. This proposal uses the recently developed strategy of the use of single peptides covalently bound to class II MHC to study the repertoire of CD4+ T cells selection in vivo. The major goal of this proposal is to test the hypothesis that in neonates the peripheral repertoire of CD4+ T cells can be controlled by neopeptide-inducible thymic selection. Therefore, in specific aim one the investigators will determine how the contact residues between the MHC/peptide complex and TCR influence the repertoire of the selected T cells. Next, the investigators will test the role of the diversity of self derived peptides on the spectrum of selected neonates in CD4+ T cells. The third specific aim will test positive selection of the transgenic TCR induced in neonates by an in vivo administration of synthetic peptide that selects this TCR. Finally, the last specific aim will evaluate whether peptides with large side chains administered in vivo can select a restricted set of new CD4+ T cells with predicted antigen specificity.
