CONTROL OF LINEAGE COMMITMENT IN DEVELOPING THYMOCYTES

这个项目的总体目标是确定在胸腺发育过程中对CD4和CD8T细胞谱系的替代承诺的分子基础。已经在小鼠中发现了一种自发的常染色体隐性突变，这种突变特异性地阻止了导致外周辅助T细胞缺陷(“辅助缺陷”，或HD小鼠)的CD4T细胞谱系的发育。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缺陷与造血系的细胞一起转移，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表型是由CD4基因阶段特异性转录调控缺陷引起的吗？3)HD小鼠成熟T细胞功能是否受损，如果是，这是由于TCR谱系、T细胞亚群分布或TCR介导的信号传递的变化？4)HD小鼠的特异性基因缺陷是什么？这一独特的突变小鼠的详细表型特征和所涉及的特定基因缺陷的鉴定有望为血统承诺的分子机制提供重要的见解。

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.