Control of Lineage Commitment in Developing Thymocytes

描述(申请人提供)：到目前为止，ThPOK在T细胞发育中的表达被认为仅限于ab T细胞谱系，特别是胸腺和外周的过渡性CD4 8lo胸腺细胞和SP CD4细胞。我们现在发现，gdTCR胸腺细胞的一部分也表达ThPOK，并且ThPOK的表达在很大程度上与激活标记CD44的表达有关。此外，ThPOK在KN6 gdTCR转基因小鼠中表达，存在高亲和力而不是低亲和力配体。这些观察结果表明，在gd胸腺细胞中诱导ThPOK是对强TCR信号的反应。值得注意的是，缺乏功能ThPOK的HD-/-小鼠在成熟的gd胸腺细胞发育方面存在严重缺陷，而表达ThPOK的小鼠则显著增加，证实了ThPOK在gd细胞成熟和/或谱系承诺中的重要作用。鉴于tcr信号和选择对gd发育的重要性仍然存在很大争议，确立thPOK在这些过程中的关键作用将是一个重大的进步。因此，在当前提案的目标1和2中，我们建议解决ThPOK在gd胸腺细胞中的诱导是否受TCR信号的直接调控，以及thPOK是否控制gd胸腺细胞的正/负选择和/或对gd谱系的承诺。有趣的是，虽然ThPOK似乎是正常的gd发育所必需的，但它在表达TCR前的DN胸腺细胞中的表达导致胸腺淋巴瘤的高发生率。在目标3中，我们建议确定个体发育中启动淋巴肿大的细胞类型和阶段，并测试gdTCR表达或gd承诺是否足以保护糖尿病肾病胸腺细胞免受ThPOK介导的淋巴肿大的影响。 与公共健康相关：目前的提案涉及T细胞发展到不同的gd谱系的过程，我们表明这是由一种名为ThPOK的关键转录因子控制的。ThPOK如何控制这一过程是未知的，也是这项提议的主题。ThPOK的表达不受调控会导致血细胞癌，因此了解其功能与健康直接相关。

DESCRIPTION (provided by applicant): Hitherto, the expression of ThPOK in T cell development was believed to be restricted to the ab T cell lineage, in particular to transitional CD4+8lo thymocytes and SP CD4 cells in the thymus and periphery. We now show that a subset of gdTCR+ thymocytes also expresses ThPOK, and that ThPOK expression correlates largely with expression of the activation marker CD44. Furthermore, ThPOK is expressed in KN6 gdTCR transgenic mice in the presence of high but not low affinity ligands. These observations suggest that ThPOK is induced in gd thymocytes in response to strong TCR signals. Significantly, HD-/- mice, which lack functional ThPOK, show a severe defect in development of mature gd thymocytes, while mice expressing ThPOK constitutively show a striking increase, establishing an important role for ThPOK in maturation and/or lineage commitment of gd cells. Given that the importance of TCR signaling and selection for gd development remains highly controversial, establishing a critical role for ThPOK in these processes would represent a significant advance. Hence in Aims 1 and 2 of the current proposal, we propose to address whether ThPOK induction in gd thymocytes is directly regulated by TCR signaling, and whether ThPOK controls positive/negative selection of gd thymocytes and/or commitment to the gd lineage. Interestingly, while ThPOK appears to be required for normal gd development, its expression in preTCR-expressing DN thymocytes leads to a high incidence of thymic lymphomas. In Aim 3 we propose to identify the cell type and stage in ontogeny at which lymphomagenesis is initiated, and test whether gdTCR expression or gd commitment are sufficient to protect DN thymocytes against ThPOK-mediated lymphomagenesis. PUBLIC HEALTH RELEVANCE: The current proposal deals with the process by which T cells develop to the distinct gd lineage, which we show is controlled by a key transcription factor called ThPOK. How ThPOK controls this process is unknown and the subject of this proposal. Unregulated expression of ThPOK causes blood cell cancer, so that understanding its function is of direct relevance to health.