Analysis of molecular mechanisms of T cell differentiation

来源于造血干细胞的T细胞前体在胸腺中增殖和分化，具有自身mhc特异性的T细胞被正向选择（正向选择），而对自身抗原具有高亲和力的T细胞被耐受（负向选择）。这些选择是根据它们的T细胞受体（TcR）进行的。为了阐明T细胞分化的分子机制，我们研究了TcR基因在小鼠骨髓、胸腺和外周血淋巴组织中的表达。BM——长期培养骨髓（LTBM）细胞的使用为研究T细胞迁移到胸腺之前的早期分化阶段提供了相关的细胞来源。我们对胸腺nde小鼠和1pr/1pr小鼠的研究表明，LTBM细胞中TcR基因出现了异常重排，这表明这些小鼠BM中的T细胞前体可能在数量和/或质量上与正常小鼠不同。胸腺-放射BM嵌合体已被用作研究成年小鼠胸腺选择性事件机制的实验模型。我们发现在放射BM嵌合体的胸腺中，携带能够识别宿主和供体表型的TcR的T细胞都被删除。外周淋巴组织——在移植了胎儿胸腺的裸鼠中研究了耐受诱导的细胞基础。胸腺上皮具有诱导对MHC II类耐受的能力，但对mls编码抗原不具有耐受能力。

T cell precursors derived from hematopoietic stem cells proliferate and differentiate in thymus, where T cells with self-MHC specificities are positively selected (positive selection) and T cells with a high affinities for self-antigens are tolerized(negative selection). These selections are carried out on the basis of their T cell receptors (TcR). To elucidate the molecular mechanism of T cell differentiation, we have investigated the expression of TcR gene in bone marrow(BM), thymus and peripheral lymphoid tissues of mice.1. BM --- The use of the long-term cultured bone marrow (LTBM) cells provided a pertinent source of cells for investigating the early phase of T cell differentiation before migration to the thymus. Our study with athymic nde mice and 1pr/1pr mice indicated abnormal rearrangememnts of TcR genes in the LTBM cells, suggesting that T cell precursors in BM of these mice may be different in quantity and/or quality from those in normal mice.2. Thymus --- Radiation BM chimeras have been used as an experimental model for investigation of mechanisms of selective events in thymxis of adult mice. We have found that both T cells bearing TcR capable of recognizing host- and donor phenotypes are deleted in the thymus of radiation BM chimeras.3. Peripheral lymphoid tissues --- The cellular basis of tolerant induction has been investigated in nude mice grafted with fetal thymus. Thymic epithelium have a capacity to induce tolerance to MHC class II but not to Mls-encoded antigens.