The role of IL-10 in stabilizing natural regulatory T cells

IL-10 在稳定天然调节性 T 细胞中的作用

基本信息

批准号：
8495226
负责人：
MITCHELL KRONENBERG
金额：
$ 43.83万
依托单位：
LA JOLLA INSTITUTE FOR IMMUNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-01 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8495226
关键词：
Asthma Autoimmune Process Boxing CD11 Antigens CD4 Positive T Lymphocytes Cell Separation Cell physiology Cells Cellular Immunology Chromatin Colitis Collaborations CpG dinucleotide DNA Methylation Data Development Disease Disease model Employee Strikes Enzymes Epigenetic Process Exposure to Future Galactose Binding Lectin Gene Expression Profile Generations Genes Genetic Harvest ITGAM gene Immune Immune response Immune system Immunotherapy In Vitro Inflammation Inflammatory Inflammatory Bowel Diseases Insulin-Dependent Diabetes Mellitus Interleukin-10 Interleukin-17 Intestines Lamina Propria Large Intestine Lymphocyte Lymphoid Cell Lymphopenia Maintenance Maps Mediating Membrane Proteins Mesentery Methods Methylation Modeling Modification Molecular Mus Myelogenous Myeloid Cells Paper Pathway interactions Patients Pattern Phenotype Population Regulatory T-Lymphocyte Reporter Reporter Genes Role Site Small Intestines Sorting - Cell Movement Spleen System T memory cell T-Lymphocyte TNF gene TNFSF4 gene Thymus Gland Tretinoin Virus Diseases Work base cell type cytokine design efficacy testing flexibility forkhead protein genetic technology histone modification in vivo loss of function lymph nodes novel paracrine prevent receptor research study transcription factor

项目摘要

Natural regulatory T cells (nTreg) differentiate to acquire FoxpS expression and suppressive function in the thymus. These cells have been thought of as a highly stable lineage, but recent work suggests that they may lose Foxp3 expression and acquire various effector functions, particularly under conditions of lymphopenia and/or inflammation. It will be important to understand the conditions under which this loss may occur, if the expansion and transfer of nTreg, or in vivo augmentation of nTreg activity, will ever be used as immune therapies. We have made the surprising observation that nTreg transferred to Rag-/- mice require exogenous IL-10 from CD11b+ intestinal myeloid cells in order to prevent colitis. The lapsed nTreg in IL-10 deficient recipients acquire a distinct THI-like cytokine secretion pattern, characterized by the secretion of IFNy, but not TNF or IL-17. The experiments in this application therefore will use genetic technologies, cellular immunology methods and in vivo disease models to better understand the molecular changes and cellular interactions that underlie the striking in vivo changes in nTreg that we have observed. We will determine if the loss of nTreg function is reversible (Aim 1), and in Aim 2 we will fully characterize the function ofthe lapsed cells, and will determine if nTreg acting in other sites also require IL-10 from cells other than lymphocytes. Additionally, in this Aim we will examine the status ofthe Foxp3 locus in lapsed Treg, and the overall pattern of epigenetic modifications in their chromatin. We will determine in Aim 3 if induced Treg (ITreg) display a similar requirement for paracrine IL-10, and if the use of more effective induction methods, such as retinoic acid or alterations induced by viral infection, can fortify iTreg so they can function without exogenous IL-10. In aim 4, we will compare CD11b+ intestinal myeloid celis from different parts ofthe mucosal immune system for their ability to stimulate the generation of ITreg and the stabilization of nTreg. In summary, the proposed experiments build on our novel preliminary findings in order to achieve a deep understanding of the pathway leading to the dangerous loss of suppressive function in nTreg, and the means by which this can be reversed or prevented.

天然调节T细胞（NTREG）区分以获取FOXP的表达和抑制功能胸腺。这些细胞被认为是一种高度稳定的谱系，但最近的工作表明它们可能会失去FOXP3表达并获得各种效应子功能，特别是在淋巴细胞减少和/或炎症。了解这种损失的条件很重要如果将使用NTREG的扩展和转移或NTREG活动的体内扩展或转移，可能会发生作为免疫疗法。我们做出了令人惊讶的观察，即Ntreg转移到抹布 - / - 小鼠为了预防结肠炎，需要从CD11b+肠髓样细胞中进行外源性IL-10。失效的Ntreg 在IL-10缺乏的接受者中 IFNY的分泌，但不分泌TNF或IL-17。因此，该应用中的实验将使用遗传技术，细胞免疫学方法和体内疾病模型，以更好地了解分子我们观察到的NTREG中醒目的体内变化的变化和细胞相互作用。我们将确定NTREG功能的损失是否可逆（AIM 1），在AIM 2中，我们将完全表征失效细胞的功能，并将确定NTREG是否在其他地点作用也需要其他细胞中的IL-10 比淋巴细胞。此外，在此目的中，我们将研究treg的Foxp3基因座的状态，其染色质中表观遗传修饰的总体模式。如果诱发的Treg，我们将在AIM 3中确定（ITREG）对旁分泌IL-10显示类似的要求，如果使用更有效的诱导方法，例如视黄酸或病毒感染引起的改变，可以强化ITREG，以便它们可以在没有的情况下发挥作用外源IL-10。在AIM 4中，我们将比较来自不同部位的CD11b+肠髓晶肠cel 粘膜免疫系统的刺激ITREG产生和NTREG稳定的能力。在总结，提出的实验以我们新颖的初步发现为基础，以实现深度了解导致NTREG抑制功能危险丧失的途径，手段可以将其逆转或预防。