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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：
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
项目类别：
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

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.

自然调节性T细胞（nTreg）分化获得FoxpS的表达和抑制功能