IN VITRO DEVELOPMENT OF T CELL PRECURSORS

这项研究的目的是获得T淋巴细胞系， 前体，并建立其在研究胸腺的机制， 发展 这种方法将使我们能够深入了解 这是创造和维持功能性免疫系统的基本过程。 有关机制的知识不仅对我们的 了解人类和动物的健康和疾病，但也将有助于 开发新的方法来对抗自身免疫性疾病。 大量的工作一直致力于研究的胸腺教育。 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阻碍 由于大量未分化的T细胞 前体 在这个提议中，我们描述了利用体外 模型系统将允许使用来自体外的群体， 作为T淋巴细胞来源的分化的胚胎干（ES）细胞 前体 使用ES衍生的细胞的优点是几倍。 首先，我们可以重复地产生大量的这些细胞。 第二、 我们可以在胚胎干细胞中引入基因变化， 在分化的后代中。 这些发展潜力 人口将得到充分的特点和他们的有用的研究， 将确定胸腺分化。 因为我们还发现 并表征了可以诱导克隆缺失的细胞系，我们将 能够观察不同亲和力的TCR和MHC之间的相互作用 其最终负责诱导胸腺耐受。

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.