Molecular and genomic control of innate γδ T cell development

先天γδ T 细胞发育的分子和基因组控制

• 批准号: 10685628
• 负责人: Maria Ciofani
• 金额: $ 37.03万
• 依托单位: RESEARCH INST OF FOX CHASE CAN CTR
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-15 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10685628
• 关键词: Area; Binding Proteins; Cell Differentiation process; Cell Fate Control; Cells; ChIP-seq; Chromosome Mapping; Clonal Expansion; DNA-Binding Proteins; Development; EGR2 gene; Elements; Embryo; Enhancers; Epigenetic Process; Equilibrium; Event; Family; Funding; Gene Expression; Generations; Genes; Genetic Recombination; Genetic Transcription; Genomics; Human; IL4 gene; Imaging technology; Immune; Individual; Inhibitor of Differentiation Proteins; Interferon Type II; Knowledge; Lead; Life; Ligands; Liver; Molecular; Mus; Nature; Neonatal; Outcome; Perinatal; Play; Population; Protein Family; Proteins; Role; Signal Transduction; Specific qualifier value; Spleen; Stereotyping; System; T-Cell Development; T-Lymphocyte; TCF3 gene; Testing; Thymus Gland; Tissues; Transgenes; Transgenic Organisms; Untranslated RNA; V(D)J Recombination; Work; cytokine; experimental study; fetal; gene regulatory network; genome-wide; in vitro Model; insight; molecular imaging; mouse genetics; mouse model; permissiveness; postnatal; programs; protein function; recruit; stem cells; transcription factor; transgene expression; γδ T cells

PROJECT SUMMARY/ABSTRACT The γδNKT (also known as NKγδT or Vδ6.3 T) lineage represents an innate type of γδT cells that is generated in the neonatal thymus and subsequently maintained throughout life in tissues such as the thymus, spleen, and liver. These cells are closely related to αβ lineage iNKT cells, which express a semi-invariant αβTCR, and together they constitute the main populations of innate-like T lymphocytes. A major function of innate-like T lymphocytes is to modulate the development and function of other immune cells including conventional T lymphocytes. γδNKT cells use a stereotyped Vγ1.1Vδ6.3 TCR; however, their ligand(s) remains unknown. The generation of γδNKT cells in the thymus is tightly controlled by the activity of E box family of DNA-binding proteins (E proteins), which play profound roles in T cell development. The activity of E proteins is inhibited by Id proteins. The Id family protein, Id3, is induced by TCR signaling in proportion to TCR signal strength and it is the Id3-E protein balance that critically regulates the generation of γδNKT cells. Work completed by this Program Project has revealed that TCR signals orchestrate genome-wide remodeling of E protein binding to a constellation of enhancers during γδT lineage specification, differentiation, and expansion. However, the identity of the critical E protein targets that control the development of individual γδ T sublineages remains a major gap in knowledge. We, together with Project 1, have identified two critical E protein targets that regulate the development of γδNKT cells: the genomic elements encoding the stereotyped Vγ1.1Vδ6.3 TCR and a transcription factor that plays a crucial role in executing the differentiation program initiated by the TCR. We now propose to elucidate the mechanism by which E-proteins regulate γδNKT development and restrict it to neonatal life. We will do so through the following aims. In aim 1, we will investigate E-protein function in regulating the recombination events responsible for generation of the Vδ6.3 TCR chain. In aim 2, we will examine the unique nature of the stereotyped Vγ1.1Vδ6.3 TCR and how E-proteins coordinate the changes in gene expression triggered by Vγ1.1Vδ6.3 TCR signals. The current proposal is built upon key observations derived from the Program Project. The proposed experiments will continue to draw the complementary expertise in the areas of TCR signaling (Project 1), mouse genetics (Project 2), in vitro modeling of mouse and human T cell development (Project 3), and genomics and molecular imaging technologies (Project 4). Our specific aims will not only lead to a better understanding of the mechanism of γδNKT development but will also provide unique insight into the general mechanisms through which E proteins control cell fate.

项目摘要/摘要 γELT（也称为NKγδT或Vδ6.3T）谱系代表在在 新生儿胸腺，随后在胸腺，脾脏等组织中保持一生 肝脏。 征兵的主要种群是先天性T淋巴细胞的主要功能。 淋巴细胞是模块化其他免疫细胞的发育和功能，包括结合T 淋巴细胞。但是，γδNKT细胞使用定型的VVγ1.1VΔ6.3TCR； 由DNA结合蛋白的E盒家族的活性紧密控制的γδNKT细胞的产生 （e蛋白），在t细胞发育中起着深刻的作用。 ID家族蛋白ID3是由TCR信号引起的TCR信号强度的诱导的，并且ITHE ID3-E 蛋白质平衡，严格调节γγNKT细胞的产生。 人们对TCR的启示表示，E蛋白与E蛋白结合到结构的结构 γδT谱系规范，分化和扩展的增强子。 蛋白质靶向控制单个γδγγδTsublineas缓解的发展的主要差距。 我们与项目1一起确定了两个关键的E蛋白靶标，这些靶标会调节γNNKT的发展 细胞：编码定型Vγ1.1Vδ6.3TCR的基因组元素和扮演A的转录因子 在执行TCR发起的区分程序中的至关重要的作用。 e蛋白调节γδNKT并将其限制为新生儿寿命的机制。 以下目的在AIM 1中，我们将调查E蛋白的功能 负责AIM 2中的VΔ6.3TCR链。 Vγ1.1Vδ6.3TCR和E蛋白如何协调Vγ1.1VΔ6.3TCR触发的基因表达的变化 当前的提案是基于计划项目得出的关键观察。 经验将继续吸引TCR信号传导（项目1），鼠标的含有专业知识 遗传学（项目2），小鼠和人类T细胞发育的体外建模（项目3）以及基因组学和 分子成像技术（项目4）。 γδNKT开发的机制，但也将通过 蛋白质控制细胞命运。