THYMIC EPITHELIAL CELL SUBSETS AND LINEAGE RELATIONSHIPS

胸腺上皮细胞亚群和谱系关系

• 批准号: 6163924
• 负责人: Ellen R Richie
• 金额: $ 19.96万
• 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/6163924
• 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进展 (TECS)是一个相互依赖的过程，在这个过程中，每个细胞的成熟 类型取决于细胞介导的互惠诱导相互作用 接触和/或溶解因素。与广泛的文献形成对比的是 关于胸腺细胞发育的特征，可用的信息要少得多 关于TEC子集的性质和功能。鉴于危急关头 TECs在T细胞发育中的作用，至关重要的是 阐明胸腺细胞和TECs相互作用的机制 发育调控。因此，这次会议的主要目标是 建议在TEC子集之间建立血统关系，并 明确T细胞祖细胞和TECs之间的相互作用 大脑皮层两种细胞类型的发育成熟 微环境。利用角蛋白(K)表达谱鉴定TEC 我们发现，与传统教条相反，大脑皮层TEC是 不是齐次的，而是包含一个主要的K8+K5子集和一个 次要K8+K5+子集。这两个皮质TEC亚群都存在于RAG-1-/- 和TCRbetax-/-胸腺，其中T细胞的发育在 CD4-8-25+44-Pre-T细胞阶段。相比之下，K8+K5+TEC在 HCD3 epsilon转基因(TG)小鼠胸腺细胞 发育受阻于较早的CD4-8-25-44+阶段。移植 RAG-1-/-肾被膜下新生hCD3epTg胸腺的表达 小鼠出现K8+K5-TECs伴随着 CD25+胸腺细胞的出现。这些数据表明，大脑皮层TEC 发展从K8+K5+前体子集发展到K8+K5-阶段 分化过程取决于T细胞谱系的承诺。 我们还表明，胸腺细胞的发育窗口 诱导hCD3 epsilon Tg小鼠正常胸腺皮质的形成 通过在TECs中强制表达Cyclin D1转基因而延伸。 到目前为止获得的结果为TEC提供了一个可信的模型 为以下方面提供基础的发展进程 可检验的假设。(1)主要位于的本原K8+K5+子集 皮质-髓质交界处含有前驱活性 功能上不同的皮质和髓质TEC隔室。一个 这一假设的必然结果是Cyclin D1转基因的表达 在K8+K5+前体促进TEC分化 胸腺细胞通过增加和/或保持 自行车赛的祖先。(2)需要T血统承诺的过程 诱导TEC前体细胞分化和扩增为两个 通过直接接触和/或阐述细胞因子而产生的皮质亚群。