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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.

天然调节性 T 细胞 (nTreg) 分化以获得 FoxpS 表达和抑制功能胸腺。这些细胞被认为是高度稳定的谱系，但最近的研究表明它们可能会失去 Foxp3 表达并获得各种效应功能，特别是在以下条件下淋巴细胞减少和/或炎症。了解这种损失的条件非常重要如果使用 nTreg 的扩增和转移或体内增强 nTreg 活性，则可能会发生作为免疫疗法。我们令人惊讶地观察到 nTreg 转移到 Rag-/- 小鼠体内需要来自 CD11b+ 肠骨髓细胞的外源性 IL-10 来预防结肠炎。失效的nTreg 在 IL-10 缺陷的接受者中，获得了一种独特的 THI 样细胞因子分泌模式，其特征是分泌 IFNγ，但不分泌 TNF 或 IL-17。因此，本申请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 体内显着变化背后的变化和细胞相互作用。我们将确定 nTreg 功能的丧失是否是可逆的（目标 1），在目标 2 中我们将充分表征失效细胞的功能，并将确定在其他位点起作用的 nTreg 是否也需要来自其他细胞的 IL-10 比淋巴细胞。此外，在这个目标中，我们将检查失效 Treg 中 Foxp3 位点的状态，以及染色质表观遗传修饰的总体模式。我们将在目标 3 中确定是否诱导 Treg (ITreg)对旁分泌IL-10表现出类似的要求，并且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，使其无需依赖即可发挥作用外源性IL-10。在目标 4 中，我们将比较来自不同部位的 CD11b+ 肠骨髓细胞粘膜免疫系统能够刺激 ITreg 的产生和 nTreg 的稳定。在总之，所提出的实验建立在我们新颖的初步发现的基础上，以实现深入的研究了解导致 nTreg 抑制功能危险丧失的途径以及方法通过它可以扭转或防止这种情况。