The role of IL-37 in human regulatory T cells

项目总结/摘要 理解外周耐受性和维持免疫系统稳态在免疫治疗中是至关重要的。 控制人类疾病。我们以前已经证明，抗炎细胞因子IL-37 参与免疫耐受，通过在抗原诱导下产生半成熟致耐受性树突状细胞（DC）， 特异性适应性免疫反应。IL-37是IL-1家族11个成员之一，也是目前已知的唯一一个 广泛的抗炎作用。在我们最近的项目中，我们发现IL-37水平在多个人中升高， 免疫细胞类型，特别是在调节性T细胞（T细胞）中。进一步的分析显示，人类Treg 在所有T细胞亚群中，细胞表达最高的IL-37水平， 与人Treg细胞中主要转录调节因子FOXP 3的表达相关。我们目前 该项目假设IL-37表达升高可稳定Treg细胞并诱导有效的免疫应答。 通过控制FOXP 3表达抑制。IL-37在小鼠中不表达，但使用转基因小鼠和 从人类供体的外周血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，我们将使用过表达IL-37及其受体的人原代Treg细胞和T细胞系。 IL-37的突变体形式，以阐明IL-37控制人Treg细胞的生物学和分子机制 功能由于我们的提案使用人类T细胞，因此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转化影响， 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.