Early Events in Human T Cell Development

在过去的五年中，转基因和基因敲除动物以及胎儿胸腺器官培养模型已经催化了显着的进展，在划定的早期小鼠T淋巴细胞生成的分子事件。可以理解的是，对人类胸腺发生的平行事件的了解远远落后于人。这部分是由于缺乏足够的培养模型用于人T细胞分化。虽然T淋巴细胞生成的一些特征在男性和小鼠之间是共享的，但也存在显着差异。例如，人和小鼠不同发育阶段的表型特性是不同的，并且TCR β链在人类胸腺个体发育中首先重排，而γ δ发育先于小鼠中α T细胞的发育。虽然在小鼠中还没有完全理解alphabeta与gammadelta谱系决定的细节，但人类的信息甚至更基本。由于上述原因，从小鼠研究中获得的信息中得出关于人胸腺生成主要事件的结论可能不合适。因此，并与人类淋巴细胞发育的计划项目的主题保持一致，我们将进行一个详细的分析，在早期人类胸腺细胞生成的分子事件。本研究的具体目标分为三个方面：一、研究方法。解决人胸腺细胞分化的步骤。二.确定α和γ δ T细胞是否来源于共同的前体或代表两个独立的谱系。三.建立一种细胞培养系统，以有效生产处于所有分化阶段的人胸腺细胞。更全面地了解T细胞是如何在人体内产生的，将有助于理解和治疗免疫缺陷疾病，T细胞恶性肿瘤和自身免疫性疾病。

During the last five years, transgenic and knock-out animals as well as fetal thymic organ culture models have catalyzed remarkable progress in the delineation of the molecular events of early murine T lymphopoiesis. Knowledge of parallel events in human thymopoiesis has understandably lagged far behind. This is in part due to a lack of adequate culture models for human T cell differentiation. While some features of T lymphopoiesis are shared between men and mice, there are also significant differences. For example, the phenotypic properties of the various developmental stages in men and mice are different and the TCRbeta chain is the first to rearrange in human thymic ontogeny, while gammadelta development precedes that of alphabeta T cells in mice. While the details of the alphabeta versus gammadelta lineage decisions are not completely understood in mice, information in humans is even more rudimentary. For the above reasons, it may not be appropriate to draw conclusions about major event in human thymopoiesis from information obtained from the study of mice. Accordingly, and in keeping with the Program Project theme of human lymphocyte development, we will undertake a detailed analysis of the molecular events in early human thymopoiesis. The proposed research is divided into three Specific Aims: I. To resolve steps in human thymocyte differentiation. II. To determine whether alphabeta and gammadelta T cells are derived from a common precursor or represent two separate lineages. III. To develop a cell culture system for the efficient production of human thymocytes at all stages of differentiation. A more complete understanding of how T cells are made in man will benefit the understanding and treatment of immunodeficiency diseases, T cell malignancies, and autoimmune diseases.