Molecular analysis for TCR-MHC-peptide interaction in thymic selection in vitro and in vivo

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The T cell repertoire is shaped by positive and negative selection through the interaction of alphabeta T cell receptor with self-peptide bound to self-major histocompatibility complex (MHC). To elucidate TCR/MHC/peptide interaction determining this reciprocal selection process, we have tried to develop in vitro and in vivo system where a single MHC/peptide ligand is expressed.First, we developed a soluble MHC molecule of which cytoplasimic domain has been replaced with glycosyl-phophatidylinositol (GPI). This molecule complexed with a single peptide was found to be expressed on the cell-surface of any cells, by just incubation the complex with cells. However, the GPI anchored MHC/peptide complex expressed on thymic epithelial cells could not support T cell differentiation.Second, we developed transgenic mouse lines expressing MHC molecules covalently bound to a single peptide at different levels in the thymus. By comparing the fate of T cells in these lines, we found that a single MHC/peptide ligand, depending on the expression level in thymus, can serve as both positively and negatively selecting ligand.