Development and function of conventional and innate T cells

常规和先天 T 细胞的发育和功能

基本信息

批准号：
10913142
负责人：
Josephine Egan
金额：
$ 46.42万
依托单位：
NATIONAL INSTITUTE ON AGING
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

项目摘要

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..

研究调节常规和先天 T 细胞的发育、维持和衰老的转录因子。转录因子 T 细胞因子 TCF-1 和 β-连环蛋白调节 NKT 细胞的发育以及分化为 NKT1、NKT2 和 NKT17 亚群。所有 NKT 细胞的生成都需要 TCF1，因为删除 TCF1 会减少 NKT 细胞的数量。 NKT 细胞发育的减少是由于前体胸腺细胞寿命缩短以及 NKT 细胞生成和选择所需的 T 细胞受体 TCR Valpha14-Jalpha18 远端基因重排和表达减少所致。优先产生 IL-4 和 IL-13 的 NKT2 细胞的分化需要 β-连环蛋白与 TCF1 的结合。 NKT2 细胞与引起哮喘有关，因此，T 细胞中 β-连环蛋白表达增强的小鼠会促进转基因小鼠的 IL-25 依赖性哮喘。正在进行的工作重点是参与这些事件的分子机制。随着 TCR γ-δ T 细胞在胸腺中成熟，TCF1 的表达下降。然而，由于胸腺细胞中 TCF1 的诱导被证明是 Notch1 信号的下游，并且由于 Notch1 对于 γ-δ T 细胞发育不是必需的，因此这就提出了这些细胞中 TCF1 调节的问题。正在进行的工作表明 TCF1 表达可能受 γ-δ T 细胞中的 E 蛋白调节。正在进行的工作将集中于了解 γ-δ T 细胞中 TCF1 的 E 蛋白依赖性调节。最后，主要努力致力于研究调节 TCF7 表达的转录因子。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Dynamic regulation of chromatin organizer SATB1 via TCR-induced alternative promoter switch during T-cell development.

T 细胞发育过程中通过 TCR 诱导的替代启动子开关动态调节染色质组织者 SATB1。

DOI：
10.1093/nar/gkaa321
发表时间：
2020
期刊：
Nucleic acids research
影响因子：
14.9
作者：
Patta,Indumathi;Madhok,Ayush;Khare,Satyajeet;Gottimukkala,KamalvishnuP;Verma,Anjali;Giri,Shilpi;Dandewad,Vishal;Seshadri,Vasudevan;Lal,Girdhari;Misra-Sen,Jyoti;Galande,Sanjeev
通讯作者：
Galande,Sanjeev

Sustained expression of pre-TCR induced beta-catenin in post-beta-selection thymocytes blocks T cell development.