Studies on the mechanism of T cell development in the thymus

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A comprehensive study on thymic T cell development was performed. The most basic problem concerning the early stage of T cell development is whether the T cell progenitors migrating into the thymus are the hematopoietic stem cells or T cell lineage committed progenitors (p-T). By using a newly established multilineage progenitor (MLP) assay system, we found that the p-T produced in the fetal liver migrate into the thymus. During the process of T cell differentiation, immature T cells change their residence in the thymus. It was found that chemokine SDF-1 plays an important role in the movement of immature T cells.At an carly stage of T cell development, thymic p-T differentiate into T cell receptor (TCR) alphabeta and TCRgammadelta lineage, although its mechanism is unlcear. It was shown that the demethylation and germ line transcription of TCRbeta gene occurs. It was also shown that the germ line transcription of TCRalpha gene is controlled by a cis element found upstream of Jalpha49.At the CD4^+CD8^+ stage, immature alphabeta lineage T cells express TCR on their surface, and enter the stages of positive and negative selections. Transgenic-knockout mouse strains were established that expressed a single MHC classII/peptide complex, and the surface phenotypes of thymocytes of these strains were investigated. It was found that the same MHC classII/peptide complex was able to be the ligand for both positive and negative selection, but the direction of the selection was determined by the expression levels. The strength of the signal through TCR influences the determination of positive and negative selections as well as of the differentiation towards CD4/CD8 lineages. It was highly suggested that such differential signals are delivered by different type of epithelial cells having antigen presenting capability, residing in different thymic microenvironment.