THYMIC EPITHELIAL CELL SUBSETS AND LINEAGE RELATIONSHIPS

胸腺上皮细胞亚群和谱系关系

• 批准号: 6510735
• 负责人: Ellen R Richie
• 金额: $ 19.87万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-03-01 至 2004-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6510735
• 关键词: T lymphocyte; bone marrow transplantation; cell cell interaction; cell differentiation; cell population study; cyclins; cytokine receptors; epithelium; gene expression; genetically modified animals; hematopoietic growth factor; insulinlike growth factor; interleukin 1; interleukin 7; keratin; laboratory mouse; organ culture; thymus; thymus transplantation; tumor necrosis factor alpha

Developmental progression of thymocytes and thymic epithelial cells (TECs) is an interdependent process in which the maturation of each cell type depends on reciprocal inductive interactions mediated by cellular contact and/or soluble factors. In contrast to the extensive literature characterizing thymocyte development, much less information is available concerning the nature and function of TEC subsets. Given the critical role played by TECs in T cell development, it is vitally important to elucidate the mechanisms by which thymocytes and TECs interact in developmental regulation. Therefore, the major objectives of this proposal are to establish lineage relationships among TEC subsets and to define the interactions between T cell progenitors and TECs that induce developmental maturation of both cell types in the cortical microenvironment. Using keratin (K) expression patterns to identify TEC subsets we find that contrary to conventional dogma, cortical TECs are not homogeneous, but instead contain a predominant K8+K5- subset and a minor K8+K5+ subset. Both cortical TEC subsets are present in Rag-1-/- and TCRbetaxdelta-/- thymi in which T-cell development is blocked at the CD4-8-25+44- pre-T cell stage. In contrast, K8+K5+TECs predominate in the thymi of hCD3epsilon transgenic (tg) mice in which thymocyte development is blocked at an earlier CD4-8-25-44+ stage. Transplantation of newborn hCD3epsilon tg thymi under the kidney capsule of Rag-1-/- mice results in the emergence of K8+K5-TECs concomitant with the appearance of CD25+ thymocytes. These data suggest that cortical TEC development proceeds from a K8+K5+ precursor subset to a K8+K5- stage in a differentiation process that depends upon T-cell lineage commitment. We also show that the developmental window during which thymocytes induce the formation of a normal thymic cortex in hCD3epsilon tg mice is extended by enforced expression of a cyclin D1 transgene in TECs. The results obtained to date suggest a plausible model for TEC developmental progression that provides the basis for the following testable hypotheses. (1) A primitive K8+K5+ subset located primarily at the cortico-medullary junction contains precursor activity for functionally distinct cortical and medullary TEC compartments. A corollary to this hypothesis is that expression of a cyclin D1 transgene in K8+K5+ precursors enhances TEC differentiation in response to thymocyte influences by increasing and/or maintaining the fraction of cycling progenitors. (2) The process of T-lineage commitment is required to induce the differentiation and expansion of TEC precursors into two cortical subsets by direct contact and/or elaboration of cytokines.

胸腺细胞和胸腺上皮细胞的发育过程 （TECs）是一个相互依赖的过程，其中每个细胞的成熟 类型取决于细胞介导的相互诱导相互作用， 接触和/或可溶性因素。与大量的文献相比， 描述胸腺细胞发育，可用的信息少得多 关于TEC子集的性质和功能。鉴于关键的 由于TEC在T细胞发育中发挥的作用， 阐明胸腺细胞和TEC相互作用的机制， 发育调节因此，本项目的主要目标 建议是在TEC子集之间建立谱系关系， 定义T细胞祖细胞和TEC之间的相互作用， 皮质中两种细胞类型的发育成熟 微环境。使用角蛋白（K）表达模式鉴定TEC 我们发现，与传统的教条相反，皮层TEC是 不是同质的，而是包含一个占主导地位的K8+K5子集和一个 次要K8+K5+亚群。两种皮层TEC亚群均存在于Rag-1-/- 和TCR β-δ-/-胸腺，其中T细胞发育在 CD 4 -8-25+44-前T细胞期。相比之下，K8+K5+ TEC占主导地位， hCD 3b转基因（tg）小鼠胸腺，其中胸腺细胞 在较早的CD 4 -8-25-44+阶段阻断发育。移植 Rag-1-/-肾被膜下新生儿hCD 3 + tg胸腺 小鼠导致K8+K5-TEC的出现，伴随着 CD 25+胸腺细胞的出现。这些数据表明，皮层TEC 发育从K8+K5+前体亚群进行到K8+K5-阶段， 一个依赖于T细胞谱系定型的分化过程。 我们还发现胸腺细胞的发育窗口期 诱导hCD 3 Ig tg小鼠中正常胸腺皮质的形成 通过在TEC中强制表达细胞周期蛋白D1转基因来延长。 迄今为止获得的结果表明，TEC的一个合理的模型 发展进程，为以下内容提供基础 可检验的假设(1)原始K8+K5+子集主要位于 皮质-髓质连接处含有前体活性， 功能上不同的皮质和髓质TEC隔室。一 该假设的推论是细胞周期蛋白D1转基因的表达 在K8+K5+前体中， 胸腺细胞通过增加和/或维持 循环祖细胞(2)T细胞系的承诺过程是必需的 诱导TEC前体分化和扩增为两个 皮质亚群通过直接接触和/或细胞因子的加工。