Elucidating the role of autocrine TNF signaling in maintaining human regulatory T cell identity

阐明自分泌 TNF 信号传导在维持人类调节性 T 细胞身份中的作用

• 批准号: BB/W001055/1
• 负责人: Margarita Dominguez-Villar
• 金额: $ 95.55万
• 依托单位: Imperial College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FW001055%2F1
• 关键词: Elucidating; role; autocrine; TNF; signaling

Regulatory T cells are a population of cells from our immune system that are in charge of controlling all other immune cells and of inhibiting immune responses that are mistakenly activated in response to self or unharmful agents. Even though they are less than 1% of all the cells in the blood, we cannot survive without them. It is therefore important to understand the mechanisms that control their function and maintenance to ensure that they function properly to avoid autoimmune reactions. We have identified that a protein called Tumor Necrosis Alpha (TNFa) is secreted by regulatory T cells, which is somewhat surprising because this protein is thought to mainly contribute to inflammation. If we delete this protein from regulatory T cells, they are unable to proliferate and maintain their characteristics. We hypothesize that the expression of TNFa by regulatory T cells is important for the proliferation and proper function of regulatory T cells. We will use several approaches and a combination of experiments performed with human cells and mouse models to test this hypothesis by answering two questions: 1) what are the mechanisms that control the expression of this protein by regulatory T cells? And 2) What is the function of TNFa secreted by regulatory T cells? The results obtained in this project will help us understand the mechanisms that regulatory T cells utilize to maintain their function and characteristics in healthy individuals and in inflammatory diseases.

调节性T细胞是我们免疫系统中的一群细胞，它们负责控制所有其他免疫细胞，并抑制因自身或无害物质而错误激活的免疫反应。尽管它们只占血液中所有细胞的不到1%，但没有它们我们就无法生存。因此，了解控制其功能和维护的机制以确保其正常运作以避免自身免疫反应是很重要的。我们已经发现一种叫做肿瘤坏死α (TNFa)的蛋白质是由调节性T细胞分泌的，这有点令人惊讶，因为这种蛋白质被认为主要是导致炎症的原因。如果我们从调节性T细胞中删除这种蛋白质，它们就无法增殖并保持其特性。我们假设调节性T细胞表达TNFa对调节性T细胞的增殖和正常功能至关重要。我们将使用几种方法，并结合人类细胞和小鼠模型进行实验，通过回答两个问题来验证这一假设：1)调节T细胞控制这种蛋白质表达的机制是什么？2)调节性T细胞分泌TNFa的功能是什么？本项目获得的结果将有助于我们了解调节性T细胞在健康个体和炎症性疾病中维持其功能和特征的机制。