Determining Regulatory Pathways That Maintain FOXP3 in Human T regulatory Cells

确定人类 T 调节细胞中维持 FOXP3 的调节途径

• 批准号: MR/T015586/1
• 负责人: Shoba Amarnath
• 金额: $ 63.69万
• 依托单位: Newcastle University
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FT015586%2F1
• 关键词: Determining; Regulatory; Pathways; Maintain; FOXP3

Autoimmune diseases such as rheumatoid arthritis (RA) and Type I diabetes are driven by over-activated immune cells. A type of immune cell called regulatory T cell (Tregs) can efficiently stop uncontrolled immune system activation and prevent autoimmune diseases. Pilot clinical trials using Tregs as a therapy for diseases such as colitis, type 1 diabetes and other immune related diseases have shown promising results. Furthermore, evidence of Treg cell function is apparent in patients with mutation in Treg specific gene called FoxP3. Foxp3 mutation results in severe autoimmune disease in humans which is known as IPEX (immunodysregulation polyendocrinopathy enteropathy X-linked) syndrome. Therefor all these observations in humans clearly demonstrate that Tregs are indispensable for controlling over-activation of the immune system.However, how Foxp3 expression in Tregs are controlled within the human body is still not fully understood. Therefore, the goal of this grant proposal is to understand how human Foxp3 is regulated.We have discovered a new regulatory molecule (asparaginyl endopeptidase; AEP) that can control Treg cell function in mice. AEP directly cleaved and degraded FoxP3 protein in Tregs and abolished their suppressive function. In addition to this observation, we also found that AEP expression in Tregs can be significantly down-regulated by a receptor on Tregs called programmed cell death receptor-1 (PD-1). By extending our mouse studies in humans, we have discovered the expression of AEP in human Tregs but its function and importance in human Treg cells is unknown. In this grant proposal, we aim to understand the function and importance of AEP in human Tregs and other T helper cell subsets. We will study whether:1. AEP controls FoxP3 in human Treg cells and whether blocking AEP increases Treg cell function2. If PD-1 and other similar coreceptors can block AEP expression in Tregs3. Determine if AEP is expressed in other T helper cell subsets in humans and test its function within these subsets.We propose that if AEP has a similar function in human Tregs, then it would be possible to target AEP in order to generate engineered Treg cell therapies that can efficiently control a variety of autoimmune disease. Such targeted therapies will enable a better quality of life for those patients who suffer from chronic autoimmune diseases. The current standard of care for these patients include global immune suppressive drugs such as corticosteroids; the long-term use of which can result in unwanted side effects. Engineered cell therapies can not only control autoimmunity but can be deleted from the body on reaching immune cell control. Success of these therapies is already apparent in the cancer field therefore providing a proof of principle for generating similar cell therapies for treating autoimmuntiy

类风湿性关节炎(RA)和I型糖尿病等自身免疫性疾病是由过度激活的免疫细胞驱动的。一种名为调节性T细胞(Tregs)的免疫细胞可以有效地阻止不受控制的免疫系统激活，预防自身免疫性疾病。使用Tregs治疗结肠炎、1型糖尿病和其他免疫相关疾病的试点临床试验显示，结果令人振奋。此外，在Treg特异基因FoxP3突变的患者中，Treg细胞功能的证据是明显的。FOXP3基因突变会导致人类严重的自身免疫性疾病，被称为免疫失调、多内分泌疾病、肠病、X连锁综合征。因此，所有这些在人类身上的观察清楚地表明，Treg对于控制免疫系统的过度激活是必不可少的。然而，Tregs中的Foxp3如何在人体内表达仍不完全清楚。因此，这项拨款计划的目标是了解人类Foxp3是如何调节的。我们发现了一种新的调节分子(天冬酰胺内肽酶；AEP)，它可以控制小鼠Treg细胞的功能。AEP直接裂解和降解Tregs中的FoxP3蛋白，并取消其抑制功能。除此之外，我们还发现Tregs上一种称为程序性细胞死亡受体-1(PD-1)的受体可以显著下调Tregs中AEP的表达。通过将我们的小鼠研究扩展到人类，我们已经发现AEP在人类Treg细胞中表达，但它在人类Treg细胞中的功能和重要性尚不清楚。在这项拨款提案中，我们的目标是了解AEP在人类树突状细胞和其他T辅助细胞亚群中的功能和重要性。我们将研究：1.AEP是否控制人Treg细胞中的FoxP3，以及阻断AEP是否增加Treg细胞的功能。如果PD-1和其他类似的辅助受体可以阻断Tregs3中AEP的表达。确定AEP是否在人类其他T辅助细胞亚群中表达，并在这些亚群中测试其功能。我们建议，如果AEP在人类Treg中具有类似的功能，那么有可能针对AEP，以产生能够有效控制各种自身免疫性疾病的工程化Treg细胞疗法。这种有针对性的治疗将使那些患有慢性自身免疫性疾病的患者能够获得更好的生活质量。目前对这些患者的护理标准包括全球免疫抑制药物，如皮质类固醇；长期使用这些药物可能会导致不想要的副作用。工程细胞疗法不仅可以控制自身免疫，而且一旦达到免疫细胞控制，就可以从体内删除。这些疗法在癌症领域的成功已经很明显，因此为产生治疗自身免疫的类似细胞疗法提供了原理证明。

项目成果

Programmed cell death-1 receptor mediated regulation of Tbet + NK1.1 - Innate Lymphoid Cells within the Tumor Microenvironment

程序性细胞死亡 1 受体介导的 Tbet NK1.1 调节 - 肿瘤微环境中的先天淋巴细胞

• DOI: 10.1101/2022.09.21.507469
• 发表时间: 2022
• 作者: Lim J

Protocols for Innate Lymphoid Cell Phenotypic and Functional Characterization: An Overview.

• DOI: 10.1007/978-1-0716-0338-3_1
• 发表时间: 2020
• 期刊: Methods in molecular biology
• 作者: Shoba Amarnath

Twenty-One Flavors of Type 1 Innate Lymphoid Cells with PD-1 (Programmed Cell Death-1 Receptor) Sprinkles

• DOI: 10.1093/discim/kyad003
• 发表时间: 2023-02
• 期刊: Discovery Immunology
• 作者: K. Smith;G. Sciumè;Shoba Amarnath

Isolation and Characterization of Innate Lymphoid Cells within the Murine Tumor Microenvironment.

小鼠肿瘤微环境中先天淋巴细胞的分离和表征。

• DOI: 10.1007/978-1-0716-0338-3_14
• 发表时间: 2020
• 期刊: Methods in molecular biology (Clifton, N.J.)
• 作者: Mallett G