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: 8377919
• 负责人: MITCHELL KRONENBERG
• 金额: $ 46.62万
• 依托单位: LA JOLLA INSTITUTE FOR IMMUNOLOGY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8377919
• 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.

天然调节性T细胞（nTreg）分化以获得FoxpS表达和抑制功能， 胸腺这些细胞一直被认为是一个高度稳定的谱系，但最近的研究表明， 可能失去Foxp 3表达并获得各种效应子功能，特别是在 淋巴细胞减少症和/或炎症。重要的是要了解这种损失的条件 如果使用nTreg的扩增和转移或nTreg活性的体内增强， 作为免疫疗法。我们已经做出了令人惊讶的观察，即nTreg转移到Rag-/-小鼠 需要来自CD 11b+肠髓样细胞的外源性IL-10以预防结肠炎。失效的nTreg 在IL-10缺乏的接受者中，获得独特的THI样细胞因子分泌模式，其特征在于： 分泌IFN γ，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 这些变化和细胞相互作用是我们观察到的nTreg体内显著变化的基础。 我们将确定nTreg功能的丧失是否可逆（目标1），并且在目标2中，我们将完全表征nTreg功能的丧失。 功能的失效细胞，并将确定是否nTreg在其他网站也需要IL-10从其他细胞 而不是淋巴细胞。此外，在本目标中，我们将检查失效Treg中Foxp 3基因座的状态， 它们染色质中表观遗传修饰的总体模式。我们将在目标3中确定诱导的Treg （ITreg）显示出对旁分泌IL-10的类似需求，如果使用更有效的诱导方法， 如视黄酸或病毒感染引起的改变，可以强化iTreg，使其能够发挥作用， 外源性IL-10。在目的4中，我们将比较来自不同部位的CD 11b+肠髓样细胞， 粘膜免疫系统中，它们刺激ITreg产生和nTreg稳定的能力。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，以实现更深层次的研究。 了解导致nTreg抑制功能危险丧失的途径，以及 通过它可以逆转或防止这种情况。