Molecular Triggers of T Helper Lineage Choice

T 辅助细胞谱系选择的分子触发因素

• 批准号: 7508052
• 负责人: Dietmar J Kappes
• 金额: $ 43.31万
• 依托单位: RESEARCH INST OF FOX CHASE CAN CTR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7508052
• 关键词: Address; Affect; Antibodies; Binding; CD8B1 gene; Cell Adhesion; Cells; Chromatin; Complement; Consensus; Defect; Development; Genetic Transcription; In Vitro; Link; Maintenance; Mediating; Molecular; Mus; Pathway interactions; Phosphoric Monoester Hydrolases; Rattus; Receptor Signaling; Repression; Role; Shapes; Staging; T-Cell Development; T-Cell Receptor; T-Lymphocyte; Testing; Translating; base; crosslink; in vivo; insight; interest; receptor; research study; thymocyte; transcription factor

Differentiation of thymocytes into alternate T killer and helper lineages is of great interest, due to its importance in shaping the T cell compartment and as a paradigm of binary lineage decisions. A growing consensus exists that lineage choice is determined instructively by differences in T cell receptor (TCR) signalling, although the molecular basis remains poorly understood. Recently, the transcription factor Zbtb7b has been identified as a "master regulator" of lineage choice, whose expression is necessary and sufficient to trigger the T helper fate. In this application, we propose to elucidate the mechanism by which TCR signaling controls lineage choice, by addressing the following questions: 1. How is repression of Zbtb7b transcription at the DP stage controlled? DP thymocytes do not express Zbtb7b, even when subjected to antibody-mediated TCR crosslinking. We will determine whether silencing of the Zbtb7b locus in DP thymocytes, as well as thymocytes undergoing commitment to the T killer lineage, is determined epigenetically or by repressive transcription factors. 2. What is the role of Ptprk in CD4 lineage commitment? T helper lineage development is specifically blocked in rats lacking the receptor Tyr phosphatase Ptprk, suggesting an essential role in mediating class II-restricted TCR signals. We will generate Ptprk-/- mice to test if Ptprk mediates a similar function in mice, and if so whether it affects CD4 lineage commitment directly. These experiments should provide insights into the molecular basis of alternate TCR signaling and the mechanism of lineage commitment.

胸腺细胞分化为替代性 T 杀伤细胞和辅助细胞谱系引起了人们极大的兴趣，因为它在塑造 T 细胞区室中的重要性以及作为二元谱系决策的范例。越来越多的共识认为，谱系选择是由 T 细胞受体 (TCR) 信号传导的差异决定的，尽管其分子基础仍知之甚少。最近，转录因子Zbtb7b已被确定为谱系选择的“主调节因子”，其表达对于触发T辅助细胞命运是必要且充分的。在本申请中，我们建议通过解决以下问题来阐明 TCR 信号传导控制谱系选择的机制： 1. DP 阶段 Zbtb7b 转录的抑制是如何控制的？即使进行抗体介导的 TCR 交联，DP 胸腺细胞也不表达 Zbtb7b。我们将确定 DP 胸腺细胞以及正在向 T 杀伤细胞谱系定型的胸腺细胞中 Zbtb7b 位点的沉默是由表观遗传决定还是由抑制性转录因子决定。 2. Ptprk 在 CD4 谱系承诺中的作用是什么？ T 辅助细胞谱系的发育在缺乏酪氨酸磷酸酶 Ptprk 受体的大鼠中被特异性阻断，这表明在介导 II 类限制性 TCR 信号中发挥着重要作用。我们将生成 Ptprk-/- 小鼠来测试 Ptprk 是否在小鼠中介导类似的功能，如果是的话，它是否会直接影响 CD4 谱系定型。这些实验应该可以深入了解替代 TCR 信号传导的分子基础和谱系定型机制。