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.

项目概要不变自然杀伤 T (iNKT) 细胞是位于边界的 T 淋巴细胞的一个子集适应性和先天免疫。它们具有高度受限的 T 细胞受体 (TCR) 检测由非经典 MHC 分子 CD1d 呈递的糖脂抗原，它们对抗原或细胞因子刺激做出快速反应。 NKT细胞在以下方面发挥着重要作用抗微生物免疫反应，并且由于它们快速产生多种细胞因子它们被认为是癌症和其他疾病的治疗剂。 NKT 细胞因其独特的机制而获得效应表型胸腺中的选择和分化。 NKT 细胞的效应命运范围 NKT细胞的控制机制才刚刚开始被人们所认识效应器命运选择完全未知。我们的研究旨在了解控制 iNKT 细胞发育的分子机制，重点关注 E 蛋白质转录因子、其抑制剂 ID 蛋白质及其下游靶标。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因子。在此拨款申请中，我们提出实验来确定 E2A 的要求在 iNKT 细胞发育中，两种过度表达和表达不足的后果推定的 E2A 靶基因 Lef1 和 Bcl6。我们的研究将对我们产生重大影响了解 NKT 细胞数量和功能如何调节。此外，我们的研究将深入了解操纵 NKT 细胞效应器命运的机制，从而从一开始就改变免疫反应。