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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（由申请人提供）：传统上，免疫系统分为适应性和先天性系统，通过使用遗传重组产生的克隆特异性抗原特异性受体与识别进化保守病原体分子的非多样性受体进行区分。前者需要更多的时间来建立一个有效的反应，但有记忆，而后者反应迅速，没有记忆。先天免疫系统的大多数组分来源于骨髓前体，而适应性免疫系统来源于淋巴前体。然而，有一些淋巴细胞跨越这些类别。经典的例子是NK细胞，淋巴细胞从CLP发展而来，但使用生殖系编码的受体识别病原体，并以致敏状态存在。在过去的几年中，越来越多的其他先天性淋巴细胞已被确定，包括ILC（先天性淋巴细胞），以及一些表达重排抗原受体的细胞，如NKT，和一些CD 34 T细胞。这些人群在正常免疫反应和病理学中的作用和意义是一个未充分探索的领域。这些先天性淋巴样细胞中的一些，特别是ILC和NKT与常规辅助T细胞共享发育和效应程序。Th 1、Th 2和Th 17程序分别与ILC 1、ILC 2、ILC 3和NKT 1、NKT 2和NKT 17程序共享属性。由于不同的小鼠品系具有显著不同的虽然这些谱系中的基因差异很大，但很明显遗传因素有助于这些替代效应物命运的分化，但决定每个群体中每个效应物类型代表性的分子机制尚不清楚，这些机制是否为不同谱系所共有。我们小组最近的实验表明，在发育中的NKT细胞中E蛋白活性的变化实质上使效应细胞谱系分化偏向。C57 BL/6胸腺细胞中E蛋白活性的增加导致从主要的NKT 1分化谱到NKT 2/NKT 17谱的变化。在这个项目中，我们将1）测试这个模型，试图通过降低DP胸腺细胞中的E蛋白活性将Balb/c小鼠中的主要NKT 2分化模式转化为NKT 1。2)分析E蛋白活性是否在ILC分化过程中起类似作用。