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.

胸腺细胞和辅助谱系的分化是二进制谱系（TCR）信号的范式，这是一个偏见的范围。命运在此应用中提出了以下问题来阐明TCR信号的选择：1。在DP阶段控制的情况下。 2。ptprk在CD4谱系承诺中的作用是什么？在小鼠中的类似功能，如果直接影响CD4谱系委员会。