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E protein activity regulates effector lineage differentiation of NKT and ILCs

E蛋白活性调节NKT和ILC的效应谱系分化

基本信息

批准号：
9247132
负责人：
Jose Alberola-Ila
金额：
$ 25.73万
依托单位：
OKLAHOMA MEDICAL RESEARCH FOUNDATION
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9247132
关键词：
Adaptive Immune System Antigen Receptors Antigens Area Bone Marrow C57BL/6 Mouse CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes Categories Cell Differentiation process Cells Characteristics Chimera organism Clinical Common Lymphoid Progenitor Cytotoxic T-Lymphocytes DNA Binding Development Dominant-Negative Mutation E protein EDN2 gene Endothelin-2 Family Flow Cytometry Generations Genetic Genetic Recombination Genetic Transcription Germ Lines Goals Helper-Inducer T-Lymphocyte Hematopoietic stem cells Immune response Immune system Inbred BALB C Mice Infection Innate Immune System Liver Lung Lymphocyte Lymphoid Lymphoid Cell Maintenance Memory Methods Modeling Molecular Mouse Strains Mus Myelogenous Natural Killer Cells Organism Pathology Pattern Play Population Production Property Protein Family Rag1 Mouse Regulation Research Role Site Spleen Subfamily lentivirinae System T-Lymphocyte Testing Thymus Gland Time Transgenic Mice arm base experimental study helix-loop-helix protein differentiation inhibitor inhibitor/antagonist interest lymph nodes novel strategies pathogen progenitor programs protein E public health relevance receptor response thymocyte transcription factor

项目摘要

DESCRIPTION (provided by applicant): Classically the immune system has been divided into adaptive and innate systems, differentiated by the use of clonally-specific antigen-specific receptors generated by genetic recombination vs. non-diverse receptors that recognize evolutionary conserved pathogen molecules. The former requires more time to mount an effective response, but has memory, while the latter responds rapidly, and has no memory. Most components of the innate immune system derive from myeloid precursors, while the adaptive immune system derives from lymphoid precursors. However, there are a number of lymphoid cells that straddle these categories. The classic example are NK cells, lymphocytes that develop from CLPs but recognize pathogen using germ line-encoded receptors and exist in a primed state. In the last few year an increasing number of other innate lymphoid cells have been identified, including ILCs (innate lymphoid cells), as well as some cells that express rearranged antigen receptors, such as NKTs, and some  T cells. The roles and significance of these populations in normal immune responses and pathology is an underexplored area of great interest. Some of these innate lymphoid cells, especially ILCs and NKTs share developmental and effector programs with conventional helper T cells. The Th1, Th2, and Th17 programs share properties with the ILC1, ILC2, ILC3 and the NKT1, NKT2, and NKT17 programs, respectively. Since different mouse strains have significantly different distributions of these lineages, it is clear that genetic factors contribute to the differentiation across these alternative effector fates, but the molecular mechanisms that determine the representation of each effector type within each population are unknown, as is whether these mechanisms are common for the different lineages. Recent experiments from our group suggest that changes in E protein activity in developing NKT cells substantially bias effector lineage differentiation. Increasing E protein activity in C57BL/6 thymocytes results in a change from a predominant NKT1 differentiation profile to a NKT2/NKT17 profile. In this project we will 1) test this model by trying to convert the predominant NKT2 differentiation pattern in Balb/c mice to NKT1 by decreasing E protein activity in DP thymocytes. 2) analyze whether E protein activity plays a similar role during ILC differentiation.

描述(申请人提供)：传统上，免疫系统被分为适应性和先天系统，通过使用由基因重组产生的克隆特异性抗原特异性受体和识别进化保守的病原体分子的非多样性受体来区分。前者需要更多的时间来建立有效的反应，但有记忆力，而后者反应迅速，没有记忆力。天然免疫系统的大部分成分来自髓系前体，而获得性免疫系统来自淋巴系前体。然而，有一些淋巴样细胞横跨这些类别。经典的例子是NK细胞，这种淋巴细胞从CLP发育而来，但使用生殖线编码的受体识别病原体，并以启动状态存在。在过去的几年里，越来越多的其他固有淋巴样细胞被发现，包括ILCs(固有淋巴样细胞)，以及一些表达重排抗原受体的细胞，如NKT和一些T细胞。这些群体在正常免疫反应和病理中的作用和意义是一个未被充分研究的领域。其中一些先天淋巴样细胞，特别是ILCs和NKT，与传统的辅助T细胞共享发育和效应程序。Th1、Th2和Th17程序分别与ILC1、ILC2、ILC3和NKT1、NKT2和NKT17程序共享属性。由于不同品系的小鼠具有显著不同的分布对于这些谱系，很明显，遗传因素有助于这些不同效应器命运的分化，但决定每个种群中每种效应器类型的代表的分子机制尚不清楚，以及这些机制是否在不同的谱系中是共同的。我们小组最近的实验表明，发育中的NKT细胞中E蛋白活性的变化实质上会影响效应细胞的谱系分化。C57BL/6胸腺细胞中E蛋白活性的增加导致从主要的NKT1分化谱转变为NKT2/NKT17谱。在这个项目中，我们将1)通过以下方式测试此模型试图通过降低胸腺细胞中E蛋白的活性，将Balb/c小鼠主要的NKT2分化模式转变为NKT1。2)分析E蛋白活性在ILC分化过程中是否起类似作用。