THYMIC ENVIRONMENT AND T CELL DIFFERENTIATION

胸腺上皮细胞（TE）的表型不同群体支持 胸腺细胞发育的不同方面，皮质TE有助于 前胸腺细胞扩增和阳性选择，以及髓质TE 参与负选择。 这种TE异质性的基础是， 介导建立这些功能和 形态上不同的上皮区室是不明确的， 它们与胸腺细胞相互作用的性质仍然知之甚少。 这里提出的研究将检查胸腺的两个相关方面， 环境和皮质TE。 第一个是关于 参与胸腺器官发生的细胞机制， 上皮细胞之间的相互作用， 导致皮质发育的移民T细胞祖细胞 胸腺环境 胸腺器官发生的体外模型将检查 选择的粘附分子参与建立一个 功能性TE室，特别强调皮质TE 群体和T细胞祖细胞的分化潜能。 的 第二个目的是了解皮质TE在阳性反应中的作用。 选择和胸腺细胞发育的其他方面。 在这些 研究，将利用新的细胞试剂， 在表型和功能上类似于皮质TE， 体外共培养系统，以再现皮质TE功能的某些方面 体外 这种体外胸腺细胞发育的方法将用于 定义TE细胞表面分子和影响T细胞的可溶性产物， 细胞发育 作为这项工作的一部分， 由这些TE细胞产生的新型细胞因子将被进一步表征， 关于该细胞因子表达模式的基本信息， 它的受体将被确定。 了解相互作用， 胸腺细胞和TE调节的发展和维护， 淋巴细胞生成环境具有重要的临床相关性， 治疗方式，这将是有益的，在扭转的影响， 影响T细胞产生的原发性或获得性免疫缺陷， 可能有助于设计延缓与年龄相关的胸腺功能丧失的方法， 功能 定义调节细胞增殖的分子和细胞相互作用 正常的淋巴细胞发育也提供了 了解这些过程的失调， 自身免疫性疾病。

Phenotypically distinct populations of thymic epithelial cells (TE) support different aspects of thymocyte development, with cortical TE contributing to prothymocyte expansion and positive selection, and medullary TE participating in negative selection. The basis for this TE heterogeneity, the interactions that mediate the establishment these functional and morphologically distinct epithelial compartments are ill-defined and the nature of their interactions with thymocytes remain poorly understood. Studies proposed here will examine two related aspects of the thymic environment and cortical TE in particular. The first is concerned with the cellular mechanisms involved in thymus organogenesis involving the interactions between epithelial cells and between epithelial cells and immigrant T cell progenitors which lead to the development of the cortical thymic environment. In vitro models of thymus organogenesis will examine the involvement of selected adhession molecules in the establishment of a functional TE compartment with particular emphasis on the cortical TE population and the differentiation potential of T cell progenitors. The second is directed at understanding the role of cortical TE in positive selection and other poximal aspects of thymocyte development. In these studies, advantage will be taken of novel cellular reagents which phenotypically and functionally resemble cortical TE and are used in an in vitro co-culture system to reproduce some aspects of cortical TE function in vitro. This in vitro approach to thymocyte development will be used to define the TE cell surface molecules and soluble products that affect T cell development. As part of this effort, the functional properties of a novel cytokine produced by these TE cells will be further characterized and basic information regarding the expression pattern of this cytokine and it's receptor will be determined. Understanding the interplay between thymocyte and TE that regulate the development and maintenance of the lymphopoietic environment has important clinical relevance and may lead to therapeutic modalities that would be beneficial in reversing the effects of primary or acquired immunodeficiencies affecting T cell production and may be useful in designing approaches to retard age-related loss of thymic function. Defining the molecules and cell interactions that regulate normal lymphocyte development also provides the knowledge necessary for an understanding of the dysregulation of these processes that contribute to autoimmune disease.