Development and function of conventional and innate T cells

调节传统T细胞和天然T细胞发育、维持和衰老的转录因子的研究。 转录因子T细胞因子TCF-1和β-连环蛋白调控NKT细胞的发育和分化为NKT1、NKT2和NKT17亚群。所有NKT细胞的产生都需要TCF1，因为TCF1的缺失使NKT细胞的数量减少。NKT细胞发育的减少是由于前体胸腺细胞寿命的缩短和T细胞受体TCR Valpha14-Jalpha18远端基因重排和表达的减少，这是NKT细胞生成和选择所必需的。β-连环蛋白与TCF1结合是NKT2细胞分化所必需的，NKT2细胞优先产生IL-4和IL-13。NKT2细胞与哮喘有关，因此，T细胞中β-连环素表达增强的小鼠在转基因小鼠中促进了IL-25依赖的哮喘。正在进行的工作集中在这些事件所涉及的分子机制上。 随着胸腺中TCRγ-Delta T细胞的成熟，TCF1的表达下降。然而，由于在胸腺细胞中TCF1的诱导被证明是Notch1信号的下游，并且由于Notch1对γ-Delta T细胞的发育不是必需的，这就提出了TCF1在这些细胞中调节的问题。正在进行的工作表明，TCF1的表达可能受E蛋白的调节。正在进行的工作将集中在了解E蛋白对伽马-德尔塔T细胞中TCF1的调节。 最后，我们致力于研究调节Tcf7表达的转录因子。

Study of transcription factors that regulate the development, maintenance and aging of conventional and innate T cells. Transcription factors T Cell Factor TCF-1 and beta-catenin regulate the development of NKT cells and differentiation into NKT1, NKT2 and NKT17 subsets. TCF1 is required for the generation of all NKT cells, as deletion of TCF1 reduces the number to NKT cells. Reduction in the development of NKT cells results from reduced lifetime of precursor thymocytes and reduced rearrangement and expression of T cell receptor TCR Valpha14-Jalpha18 distal genes that are required for NKT cell generation and selection. Beta-catenin in conjunction with TCF1 is required for differentiation of NKT2 cells that preferentially produce IL-4 and IL-13. NKT2 cells are implicated in causing asthma, and accordingly, mice with enhanced expression of beta-catenin in T cells promote IL-25-dependent asthma in transgenic mice. Ongoing work focuses on molecular mechanisms involved in these events. Expression of TCF1 declines as TCR gamma-delta T cells mature in the thymus. However, as induction of TCF1 in thymocytes was shown to be down-stream of Notch1 signals and, since Notch1 is not essential for gamma-delta T cell development, this raised the question of TCF1 regulation in these cells. Ongoing work indicates that TCF1 expression maybe regulated by E-proteins in gamma-delta T cells. Ongoing work will focus on understanding E-protein dependent regulation of TCF1 in gamma-delta T cells. Finally, a major effort is devoted to studying transcription factors that regulate expression of TCF7..