REGULATORY EVENTS IN T CELL DEVELOPMENT IN THE THYMUS

该项目旨在发现重要的 调节分子，控制T细胞的发育， 胸腺和外周免疫反应。众所周知，血液 前体细胞出现在胚胎区域， 小鼠胚胎发生第10/11天的胸腺。这些细胞 通过一系列的发展阶段， 成熟的T最终需要的各种能力 细胞进行适当的免疫功能。我们和其他人已经 显示来自形成细胞间质壳的信号， 胸腺提供信号使前体细胞变成T细胞 而不是其他类型的淋巴细胞，如B或自然杀伤细胞 (NK)细胞我们发现最早的胸腺前体细胞 被称为NK1.1的细胞表面蛋白细分， 来识别那些致力于成为T细胞的细胞 细胞我们还确定了p53分子作为一个检查点， 胸腺发育一旦前体细胞已经致力于 变成T细胞。最后，我们成功地找到了 小鼠中信号分子Ly-GDI和RLK的敲除 其在发育中的胸腺细胞中高度表达。 有趣的是，这些基因的纯合缺陷并没有 可检测地改变胸腺细胞发育， 成熟T细胞的功能异常。特别是，我们的数据 表明RLK基因是一种酪氨酸激酶， 帮助T细胞对抗感染。这些结果可能具有重要意义 骨髓移植与免疫缺陷 涉及T细胞的疾病。

This project is designed to discover important regulatory molecules that control T cell development within the thymus and peripheral immune responses. It is known that blood precursor cells appear in the embryonic region that will become the thymus at day 10/11 of embryogenesis in the mouse. These cells go through a series of developmental stages during which they acquire various capacities that will be eventually needed by the mature T cell to carry out appropriate immune functions. We and others have shown that signals from the cells that form the stromal shell of the thymus provide signals to cause the precursor cells to become T cells and not other types of lymphocytes such as B or natural killer (NK) cells. We have found that the earliest thymic precursors can be subdivided by a cell surface protein called NK1.1 that allows us to identify cells that have committed themselves to becoming T cells. We have also identified the p53 molecule as a checkpoint in thymic development once the precursor cells have committed to becoming T cells. Finally, we have succeeded in pursuing gene knock-outs in mice for the signalling molecules Ly-GDI and RLK which are highly expressed within developing thymocytes. Interestingly, homozygous deficiencies of these genes did not detectably alter thymocyte development but rather caused functional abnormalities in mature T cells. In particular, our data show that the RLK gene is a tyrosine kinase that plays a role in helping T cells to fight infections. These results may have important implications for bone marrow transplantation and immunodeficiency diseases involving T cells.