Mechanisms of E protein transcription factor-dependent iNKT cell expansion and differentiation

E蛋白转录因子依赖性iNKT细胞扩增和分化的机制

基本信息

批准号：
10065488
负责人：
BARBARA L. KEE
金额：
$ 39.9万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-12-19 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10065488
关键词：
Antigens Applications Grants Asthma Atherosclerosis Autoimmune Diseases Autoimmunity BCL6 gene CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes CD8B1 gene Cell Count Cell Differentiation process Cell Lineage Cell physiology Cells Cytotoxic T-Lymphocytes Data Dendritic Cells Development Disease E protein Ectopic Expression Effector Cell Ensure Failure GATA3 gene Gene Expression Gene Expression Profile Genes Genetic Transcription Glycolipids Grant Hypersensitivity ID2 gene IL17 gene IL4 gene IL7 gene IgE Immune Immune response Immune system Inhibitor of Differentiation Proteins Insulin-Dependent Diabetes Mellitus Intercept Interferon Type II Invaded Malignant Neoplasms Memory Molecular Multiple Sclerosis Mus Natural Immunity Phenotype Play Population Predisposition Production Proteins Regulation Repression Research Rheumatoid Arthritis Role Serum Specific qualifier value System Systemic Lupus Erythematosus T-Cell Development T-Cell Receptor T-Lymphocyte T-Lymphocyte Subsets TCF3 gene Testing Therapeutic Therapeutic Agents Thymus Gland Tuberculosis WNT Signaling Pathway ZNF145 gene adaptive immunity antimicrobial base c-myc Proto-Oncogenes cell type cytokine experimental study graft vs host disease in vivo in vivo Model inhibitor/antagonist insight mutant novel pathogen thymocyte transcription factor

项目摘要

Project Summary Invariant natural killer T (iNKT) cells are a subset of T lymphocytes that sit at the boarder of adaptive and innate immunity. They have highly restricted T cell receptors (TCRs) that detect glycolipid antigen presented by the non-classical MHC molecule CD1d and they respond rapidly to antigen or cytokine stimulation. NKT cells play an important role in anti-microbial immune responses and because of their rapid production of multiple cytokines they are being considered as therapeutic agents in cancer and other diseases. NKT cells acquire their effector phenotype as a consequence of their unique mechanism of selection and differentiation in the thymus. The range of effector fates that NKT cells can acquire is only beginning to be appreciated but the mechanisms controlling NKT cell effector fate choice are completely unknown. Our research is directed at understanding the molecular mechanisms that control iNKT cell development with a focus on the E protein transcription factors, their inhibitors the ID proteins, and their downstream targets. These proteins are critical regulators of iNKT cell numbers and effector cell fate choice. In this grant application we propose experiments to determine the requirements for E2A in iNKT cell development an the consequences of over- and under-expression of two putative E2A target genes, Lef1 and Bcl6. Our studies will have a major impact on our understanding of how NKT cell number and function is regulated. In addition, our studies will provide insight into mechanisms to manipulate NKT cell effector fate and thereby alter immune responses at their inception.

项目摘要不变的天然杀手t（Inkt）细胞是位于寄宿生的T淋巴细胞的子集适应性和先天免疫。他们具有高度限制的T细胞受体（TCR）检测非经典MHC分子CD1D呈现的糖脂抗原，它们对抗原或细胞因子刺激的反应迅速。 NKT细胞在抗微生物免疫反应，并且由于其迅速产生多重反应细胞因子它们被认为是癌症和其他疾病中的治疗剂。 NKT细胞由于其独特的机制而获得其效应器表型胸腺的选择和分化。 NKT细胞的效应命运范围可以收购才开始被欣赏，但是控制NKT单元的机制效应命运的选择是完全未知的。我们的研究旨在理解控制INKT细胞发育的分子机制，重点是E 蛋白质转录因子，其抑制作用ID蛋白及其下游靶标。这些蛋白质是INKT细胞数量和效应细胞命运选择的关键调节剂。在此赠款申请中，我们建议实验以确定E2A的要求在inkt细胞开发中，两个推定的E2A靶基因LEF1和BCL6。我们的研究将对我们的了解如何调节NKT单元格的数量和功能。此外，我们的研究将提供有关操纵NKT细胞效应子命运的机制的洞察力在成立时改变免疫反应。