Control of Lineage Commitment in Developing Thymocytes

描述（由申请人提供）：目前，认为ThPOK在T细胞发育中的表达限于ab T细胞谱系，特别是胸腺和外周中的过渡性CD 4 +8lo胸腺细胞和SP CD 4细胞。我们现在表明，一个子集的gdTCR+胸腺细胞也表达ThPOK，和ThPOK的表达在很大程度上与活化标志物CD 44的表达相关。此外，在存在高亲和力而非低亲和力配体的情况下，ThPOK在KN 6 gdTCR转基因小鼠中表达。这些观察结果表明，ThPOK诱导gd胸腺细胞响应强TCR信号。值得注意的是，缺乏功能性ThPOK的HD-/-小鼠在成熟gd胸腺细胞的发育中显示出严重缺陷，而组成性表达ThPOK的小鼠显示出显著增加，确立了ThPOK在gd细胞成熟和/或谱系定型中的重要作用。鉴于TCR信号传导和选择对gd发育的重要性仍然存在高度争议，建立ThPOK在这些过程中的关键作用将代表一个重大进展。因此，在当前提案的目的1和2中，我们提出解决gd胸腺细胞中的ThPOK诱导是否直接受TCR信号传导调节，以及ThPOK是否控制gd胸腺细胞的正/负选择和/或对gd谱系的定型。有趣的是，虽然ThPOK似乎是正常gd发育所需的，但其在表达前TCR的DN胸腺细胞中的表达导致胸腺淋巴瘤的高发病率。在目的3中，我们提出了确定淋巴瘤发生启动的细胞类型和个体发育阶段，并测试gdTCR表达或gd定型是否足以保护DN胸腺细胞免受ThPOK介导的淋巴瘤发生。 公共卫生相关性：目前的提议涉及T细胞发育为不同的gd谱系的过程，我们表明这是由一种称为ThPOK的关键转录因子控制的。ThPOK如何控制这一过程是未知的，也是本提案的主题。ThPOK的不受调节的表达导致血细胞癌，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.