CONTROL OF LINEAGE COMMITMENT IN DEVELOPING THYMOCYTES

该项目的总体目标是确定胸腺发育过程中CD4和CD8 T细胞谱系替代定型的分子基础。 已经在小鼠中鉴定了自发性常染色体隐性突变，其特异性地消除了导致外周辅助性T细胞缺乏症的CD4 T细胞谱系的发育（“辅助性缺乏症”或HD小鼠）。 CD4和II类基因座的突变被明确排除为表型的原因，表明它代表了一种新的基因缺陷。 HD缺陷与造血谱系的细胞一起转移，并且似乎是发育中的胸腺细胞所固有的。 目前的建议解决了以下关于HD小鼠的具体问题：1）HD小鼠中I类和II类限制性胸腺细胞的发育命运是什么？2)HD表型是否由CD4基因的阶段特异性转录调控缺陷引起？，3)HD小鼠的成熟T细胞功能是否受损，如果是，这是否是由于TCR库、T细胞亚群分布或TCR介导的信号传导的改变？4)HD小鼠的特定基因缺陷是什么？提出的详细的表型表征这种独特的突变小鼠和识别特定的基因缺陷，预计将提供显着的见解，潜在的谱系承诺的分子机制。

The general aim of this project is to define the molecular basis of alternative commitment to the CD4 and CD8 T cell lineages during thymic development. A spontaneous autosomal recessive mutation has been identified in mice that specifically abrogates development of the CD4 T cell lineage causing a peripheral helper T cell deficiency ("helper deficient," or HD mice). Mutations at the CD4 and class II loci are specifically excluded as the cause of the phenotype, indicating that it represents a novel gene defect. The HD defect is transferred with cells of the hematopoietic lineage, and appears to be intrinsic to developing thymocytes. The current proposal addresses the following specific questions with regard to HD mice: 1) What are the developmental fates of class I- and II-restricted thymocytes in HD mice?, 2) Is the HD phenotype caused by a defect in stage- specific transcriptional regulation of the CD4 gene?, 3) Is mature T cell function impaired in HD mice, and if so is this due to alterations in TCR repertoire, T cell subset distribution or TCR-mediated signalling?, 4) What is the specific gene defect in HD mice? The proposed detailed phenotypic characterization of this unique mutant mouse and identification of the specific gene defect involved are expected to provide significant insights into the molecular mechanisms underlying lineage commitment.