IN VITRO DEVELOPMENT OF T CELL PRECURSORS

这项研究的目的是为了获得T淋巴细胞系 前体及其在胸腺机制研究中的应用 发展。这种方法论将使我们能够洞察 产生和维持功能免疫系统的基本过程。 对所涉及的机制的了解不仅对我们的 了解人类和动物的健康和疾病，但也会有所帮助 开发抗击自身免疫性疾病的新方法。 已有大量工作致力于胸腺教育的研究。 然而，T淋巴细胞分化的几个方面仍然存在 无法解释。旨在解决这些问题的研究受到了阻碍。 由于大量未分化的T细胞无法获得 先驱物。在这项建议中，我们描述了利用体外培养的实验 将允许使用来自体外的种群的模型系统 分化的胚胎干细胞作为T淋巴细胞的来源 先驱物。使用胚胎干细胞的优势是多方面的。 首先，我们可以重复地产生大量这样的细胞。第二, 我们可以在ES细胞中引入基因变化并分析它们的影响 在分化的后代中。这些项目的发展潜力 将充分描述种群的特征及其在查看时的有用信息 胸腺分化将被确定。因为我们还确认了 以及可以诱导克隆删除的细胞系，我们将 能够观察不同亲和力的TCR和MHC之间的相互作用 它们最终导致了胸腺耐受性。

The aim of the proposed study is to derive lines of T lymphocyte precursors and to establish their use in studying mechanisms of thymic development. This methodology will enable us to gain insight into fundamental processes that create and sustain a functional immune system. The knowledge of the mechanisms involved is crucial not only to our understanding of human and animal health and illness, but will also help to develop novel approaches to fight auto-immune diseases. A large body of work has been devoted to the study of thymic education. However, several aspects of T lymphocyte differentiation still remain unexplained. Studies aimed at addressing these issues have been hampered by the inaccessibility of significant numbers of undifferentiated T cell precursors. In this proposal, we describe experiments utilizing in vitro model systems that will allow the use populations derived from in vitro differentiated embryonic stem(ES) cells as source of T lymphocyte precursors. The advantage of using ES-derived cells are several fold. First, we can generate large numbers of these cells reproducibly. Second, we can introduce genetic changes in the ES cells and analyze their effects within the differentiating progeny. The developmental potential of these populations will be fully characterized and their useful in looking at thymic differentiation will be determined. Since we have also identified and characterized cell lines that can induce clonal deletion, we will be able to look at interactions between TCR and MHC of different affinity which ultimately are responsible for inducing thymic tolerance.