Regulation of NKT cell development and function by c-Myb

c-Myb 对 NKT 细胞发育和功能的调节

基本信息

批准号：
8032491
负责人：
Jose Alberola-Ila
金额：
$ 20.17万
依托单位：
OKLAHOMA MEDICAL RESEARCH FOUNDATION
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-03-01 至 2013-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8032491
关键词：
Adoptive Transfer Antigens Ants Atherosclerosis Autoimmune Diseases Autoimmune Process Autoimmunity Breeding CD8B1 gene Cell Adhesion Molecules Cell Differentiation process Cells Characteristics Communicable Diseases Complement Cues DNA Sequence Rearrangement Data Defect Dendritic Cells Development Diabetes Mellitus Disease Family Generations Genes Genetic Glycolipids Grant Half-Life Hematopoiesis Hematopoietic Histocompatibility Antigens Class I Homeostasis Hour Hypersensitivity Immune response Immune system In Vitro Knowledge Lupus Lymphocyte Subset MYB gene Malignant Neoplasms Molecular Mus Natural Killer Cells Pathogenesis Phenotype Play Process Production Proto-Oncogene Proteins c-myb Regulation Retroviridae Role Running Secondary to Signal Pathway Signal Transduction T-Lymphocyte T-Lymphocyte Subsets Tamoxifen Testing Time Transgenic Mice Transgenic Organisms Tumor Immunity behavior influence cancer therapy chemokine cytokine cytotoxic in vivo macrophage member microbial neutrophil pathogen public health relevance research study response thymocyte transcription factor

项目摘要

DESCRIPTION (provided by applicant): NKT cells represent a distinct subset of T lymphocytes that recognize glycolipid antigens presented by the nonclassical MHC class I molecule CD1d. Antigen recognition by NKT cells results in a "cytokine storm"; the secretion, within hours, of large quantities of Th1 and Th2 cytokines and chemokines, reminiscent of innate rather than adaptive functions. Through this cytokine and chemokine production, NKT cells influence the behavior of many other cells in the immune system, including NK cells, macrophages, other 12 T cells, dendritic cells and neutrophiles, and have been implicated in multiple processes, including microbial immunity, and tumor rejection. Similarly, they seem to play a role in the pathogenesis of autoimmune processes, atherosclerosis and allergy. Our results demonstrate that c-Myb, a transcription factor that plays multiple roles in hematopoiesis, is a critical player in NKT cell development. Inducible deletion of c-Myb in DP thymocytes results in a complete blockade in NKT cell development, previous to positive selection. Preliminary evidence suggests that different mechanisms may be responsible for this effect. c-Myb: thymocytes have a shortened half-life, have defects in TcR1 rearrangement -that may be secondary to the defect in half-life- and have defects in the expression of members of the SLAM/SAP signaling pathway, which is required for NKT cell positive selection. In aim one of this grant we propose experiments to analyze in detail the contributions of these mechanisms to the final phenotype of c-Myb: thymocytes. In aim two we will delete c-Myb from mature NKT cells and analyze its contribution to mature NKT cell homeostasis and function. PUBLIC HEALTH RELEVANCE: NKT cells are a distinct subset of lymphocytes that play an important role in immune responses against pathogens. Alterations in their function may play a role in the pathogenesis of autoimmune disorders such as lupus or diabetes, as well as in atherosclerosis. This project will analyze the role of c-Myb, a transcription factor, in the development and function of NKT cells. A better understanding of these processes may offer clues to their manipulation during disease.

描述（由申请人提供）：NKT 细胞代表 T 淋巴细胞的独特子集，其识别由非经典 MHC I 类分子 CD1d 呈递的糖脂抗原。 NKT 细胞识别抗原会导致“细胞因子风暴”；数小时内分泌大量 Th1 和 Th2 细胞因子和趋化因子，让人想起先天功能而不是适应性功能。通过产生这种细胞因子和趋化因子，NKT 细胞影响免疫系统中许多其他细胞的行为，包括 NK 细胞、巨噬细胞、其他 12 种 T 细胞、树突状细胞和中性粒细胞，并参与多种过程，包括微生物免疫和免疫系统。肿瘤排斥。同样，它们似乎在自身免疫过程、动脉粥样硬化和过敏的发病机制中发挥着作用。我们的结果表明，c-Myb 是一种在造血过程中发挥多种作用的转录因子，是 NKT 细胞发育的关键参与者。 DP 胸腺细胞中 c-Myb 的诱导缺失会导致 NKT 细胞发育完全受阻，然后进行正选择。初步证据表明，不同的机制可能造成这种效应。 c-Myb：胸腺细胞半衰期缩短，TcR1 重排存在缺陷（可能继发于半衰期缺陷），并且 SLAM/SAP 信号通路成员的表达存在缺陷，这是NKT细胞正选择。在这项资助的目标之一中，我们提出了实验来详细分析这些机制对 c-Myb 最终表型：胸腺细胞的贡献。在目标二中，我们将从成熟 NKT 细胞中删除 c-Myb，并分析其对成熟 NKT 细胞稳态和功能的贡献。公共卫生相关性：NKT 细胞是淋巴细胞的一个独特子集，在针对病原体的免疫反应中发挥着重要作用。它们功能的改变可能在狼疮或糖尿病等自身免疫性疾病以及动脉粥样硬化的发病机制中发挥作用。该项目将分析转录因子 c-Myb 在 NKT 细胞的发育和功能中的作用。更好地了解这些过程可能会为疾病期间的操纵提供线索。