The role of IL-37 in human regulatory T cells

项目摘要/摘要 了解外周耐受和维持免疫系统的动态平衡在 控制人类疾病。我们之前已经证明了抗炎细胞因子IL-37 通过在抗原中产生半成熟的致耐受树突状细胞(DC)参与免疫耐受- 特定的适应性免疫反应。IL-37是IL-1家族的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，我们发现在多名人类中IL-37水平升高 免疫细胞类型，特别是调节性T细胞(Tregs)。进一步的分析表明，人类的特雷格 在所有T细胞亚群中，细胞表达IL-37的水平最高，细胞内表达的IL-37 与人Treg细胞中转录主控因子FOXP3的表达有关。我们目前的情况 该项目假设IL-37表达增加可以稳定Treg细胞并诱导强大的免疫 通过控制FOXP3的表达进行抑制。IL-37在小鼠体内不表达，但使用转基因小鼠和 从人类捐献者的外周血T细胞中，我们产生了强有力的初步数据来支持我们的假设。 在这项拨款提案中，我们将使用人类原代Treg细胞和过表达IL-37和其 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。因为我们的方案使用了人类T细胞，所以结果可以很容易地转化为临床医学 和病人护理。我们的发现将对许多人类疾病产生巨大的翻译影响，例如 自身免疫和移植。

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.