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

• 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
• 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

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.

自然调节性T细胞(NTreg)分化获得FoxpS表达和抑制功能 胸腺。这些细胞一直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的表达并获得各种效应器功能，特别是在以下情况下 淋巴细胞减少和/或炎症。重要的是要了解这种损失在什么情况下 如果将使用nTreg的扩增和转移，或体内nTreg活性的增强，则可能会发生 作为免疫疗法。我们做出了令人惊讶的观察，nTreg转移到RAG-/-小鼠身上 需要CD11b+肠道髓系细胞外源性IL-10才能预防结肠炎。不复存在的nTreg 在IL-10缺乏的受者中，获得了一种独特的Thi样细胞因子分泌模式，其特征是 分泌干扰素，但不分泌肿瘤坏死因子或白介素17。因此，此应用程序中的实验将使用基因 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在体内的惊人变化背后的变化和细胞相互作用。 我们将确定nTreg功能的丧失是否可逆(目标1)，在目标2中，我们将全面描述 并将确定作用于其他部位的nTreg是否也需要来自其他细胞的IL-10 而不是淋巴细胞。此外，在这个目标中，我们将检查失效的Treg中Foxp3基因座的状态，以及 它们染色质的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也有类似的要求，如果使用更有效的诱导方法， 如维甲酸或病毒感染引起的改变，可以增强iTreg，使其在没有病毒感染的情况下也能发挥作用 外源性IL-10。在目标4中，我们将比较来自不同部位的CD11b+肠髓系细胞。 黏膜免疫系统具有刺激ITreg生成和稳定nTreg的能力。在……里面 综上所述，拟议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 对nTreg中危险的抑制功能丧失的途径和方法的理解 可以通过它来逆转或防止这种情况。