Studies on the mechanism of T cell development in the thymus

对胸腺T细胞发育进行了全面研究。关于T细胞发育的早期阶段的最基本的问题是迁移到胸腺中的T细胞祖细胞是造血干细胞还是T细胞谱系定向祖细胞（p-T）。利用新建立的多系祖细胞（MLP）检测系统，我们发现胎肝产生的p-T迁移到胸腺。在T细胞分化过程中，未成熟T细胞改变其在胸腺中的居住地。研究发现趋化因子SDF-1在未成熟T细胞的运动中起重要作用，在T细胞发育的早期，胸腺p-T细胞分化为T细胞受体（TCR）α和TCR γ δ谱系，但其机制尚不清楚。结果表明，TCR β基因发生去甲基化和生殖系转录。在CD 4 ^+ CD 8 ^+阶段，未成熟的α系T细胞在其表面表达TCR，并进入正选择和负选择阶段。转基因敲除小鼠品系的建立，表达一个单一的MHC II类/肽复合物，这些菌株的胸腺细胞的表面表型进行了研究。发现相同的MHC II类/肽复合物能够作为阳性和阴性选择的配体，但选择的方向由表达水平决定。通过TCR的信号强度影响阳性和阴性选择的确定以及向CD 4/CD 8谱系的分化。强烈建议这种差异信号由具有抗原呈递能力的不同类型的上皮细胞递送，其驻留在不同的胸腺微环境中。

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.