The role of IL-37 in human regulatory T cells

IL-37 在人类调节性 T 细胞中的作用

基本信息

批准号：
10445346
负责人：
Mayumi Fujita
金额：
$ 59.4万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-06 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10445346
关键词：
Anti-Inflammatory Agents Antigens Applications Grants Autoimmunity Binding Biological Biology Blood Cells CASP1 gene Cell Line Cell Nucleus Cell physiology Cells Clinical Clinical Medicine Complex DNA Data Dendritic Cells Exposure to FOXP3 gene Failure Family member Foundations Generations Genetic Transcription Graft Rejection Heterogeneity Homeostasis Human Human Engineering IL2RA gene Immune Immune Tolerance Immune system Immunosuppression In Vitro Individual Inflammasome Inflammatory Interleukin-1 Investigation Laboratory mice Lead MADH2 gene MADH3 gene Maintenance Mediating Messenger RNA Molecular Mus Pathology Patient Care Pharmacology Phenotype Process Regulatory T-Lymphocyte Reporting Role Signal Pathway Species Specificity T-Lymphocyte T-Lymphocyte Subsets Testing Therapeutic Transcriptional Regulation Transgenic Mice Transgenic Organisms Translating Translational Regulation Transplantation Tumor Immunity adaptive immune response cell type cellular engineering clinical application cytokine exposed human population extracellular forkhead protein human disease humanized mouse in vivo member mouse model mutant overexpression peripheral blood peripheral tolerance phenotypic biomarker prevent promoter protein complex tissue injury tool transcription factor translational impact

项目摘要

PROJECT SUMMARY/ABSTRACT Understanding peripheral tolerance and the maintenance of immune system homeostasis are vital in the control of human diseases. We have previously demonstrated that anti-inflammatory cytokine IL-37 participates in immune tolerance by generating semi-mature tolerogenic dendritic cells (DCs) in antigen- specific adaptive immune responses. IL-37 is one of eleven IL-1 family members and the only known member to be broadly anti-inflammatory. In our recent project, we found IL-37 levels were elevated in multiple human immune cell types, specifically in regulatory T cells (Tregs) cells. Further analysis revealed that human Treg cells express the highest IL-37 levels among all T-cell subsets and that intracellular expression of IL-37 correlates with the expression of master transcriptional regulator, FOXP3, in human Treg cells. Our current project hypothesizes that elevated IL-37 expression stabilizes Treg cells and induces potent immune suppression by controlling FOXP3 expression. IL-37 is not expressed in mice, but using transgenic mice and peripheral blood T cells from human donors, we generated strong preliminary data to support our hypothesis. In this grant proposal, we will use human primary Treg cells and T cell lines overexpressing IL-37 and its mutant form to elucidate the biological and molecular mechanisms of IL-37 in controlling human Treg cell function. Since our proposal uses human T cells, the results could be easily translated into clinical medicine and patient care. Our findings will have an immense translational impact on many human diseases such as autoimmunity and transplantation.

项目概要/摘要了解外周耐受性和维持免疫系统稳态对于免疫系统至关重要控制人类疾病。我们之前已经证明抗炎细胞因子IL-37 通过在抗原中产生半成熟的耐受性树突状细胞（DC）来参与免疫耐受特异性适应性免疫反应。 IL-37 是 IL-1 家族 11 个成员之一，也是唯一已知的成员具有广泛的抗炎作用。在我们最近的项目中，我们发现多种人类体内 IL-37 水平升高免疫细胞类型，特别是调节性 T 细胞 (Treg) 细胞。进一步分析表明，人类 Treg 在所有 T 细胞亚群中，细胞表达的 IL-37 水平最高，并且 IL-37 的细胞内表达与人 Treg 细胞中主转录调节因子 FOXP3 的表达相关。我们目前的该项目假设 IL-37 表达升高可以稳定 Treg 细胞并诱导有效的免疫通过控制 FOXP3 表达来抑制。 IL-37不在小鼠体内表达，但使用转基因小鼠和通过使用来自人类捐赠者的外周血 T 细胞，我们生成了强有力的初步数据来支持我们的假设。在这项资助提案中，我们将使用人类原代 Treg 细胞和过表达 IL-37 及其突变形式阐明IL-37控制人Treg细胞的生物学和分子机制功能。由于我们的建议使用人类 T 细胞，因此结果可以轻松转化为临床医学和病人护理。我们的发现将对许多人类疾病产生巨大的转化影响，例如自身免疫和移植。