Role of DEPTOR in T Cell Activation and Alloimmunity

DEPTOR 在 T 细胞激活和同种免疫中的作用

• 批准号: 10302288
• 负责人: David M. Briscoe
• 金额: $ 57.53万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-12-08 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10302288
• 关键词: Acute; Address; Allografting; Antigens; Area; Biological; Biological Response Modifier Therapy; Biology; CD4 Positive T Lymphocytes; Cell Communication; Cell Differentiation process; Cell physiology; Cells; Cellular Metabolic Process; Chronic; Development; Disease; Eragrostis; Excision; FOXP3 gene; FRAP1 gene; Funding; Graft Rejection; Graft Survival; Immunobiology; Immunosuppression; In Vitro; Individual; Intrinsic factor; Knock-in Mouse; Knockout Mice; Life; Link; Literature; Metabolic Pathway; Metabolism; Modeling; Normal Cell; Organ Transplantation; Outcome; Pathologic; Pharmacology; Phenotype; Physiological; Prevention; Process; Regulation; Regulatory T-Lymphocyte; Research; Research Proposals; Role; Savings; Signal Transduction; Sirolimus; T cell differentiation; T-Cell Activation; T-Lymphocyte Subsets; Testing; Therapeutic; Transgenic Mice; Transgenic Organisms; Transplantation; Ubiquitination; Vascular Endothelial Cell; allograft rejection; cancer cell; cell type; clinically relevant; cohesion; effector T cell; end-stage organ failure; functional outcomes; genetic regulatory protein; immunoregulation; in vivo; in vivo Model; inhibitor; innovation; insight; isoimmunity; mTOR Inhibitor; novel; overexpression; prevent; response; small molecule; transplant model

Project Summary/Abstract Allograft rejection is characterized by effector CD4+ T cell activation in response to donor antigen and an intense cellular and humoral attack on the graft. However, multiple intracellular signals within CD4+ T cells operate co-incidentally to enhance the expansion and function of CD4+Foxp3+ T regulatory cells that collectively serve to control the alloimmune response. Furthermore, the potency of this process of immunoregulation prevents and restrains alloimmune T effector cell activation and rejection. Importantly, recent advances indicate that CD4+Foxp3+ T cell differentiation and function is negatively regulated by the cell intrinsic activity of mTOR and specifically mTORC1. However, little is known about the regulation of intracellular mTOR signaling within alloreactive CD4+ T cell effectors, or how its relative activity may be modulated in Foxp3+ subsets, or whether it is possible to exploit modulatory signals to augment physiological Treg activity in pathological states to prevent disease, including the development of chronic allograft rejection. DEPTOR is a recently discovered cell intrinsic factor that modulates mTOR-induced signaling responses in highly proliferative cancer cells, and it has more recently been observed to function in normal cell types including vascular endothelial cells. In preliminary studies, we find that DEPTOR is expressed at high levels in unactivated CD4+ T cells, and further, that its expression is reduced upon cellular activation. In addition, we find that forced overexpression of DEPTOR modulates CD4+ T cell activation responses in vitro, promotes immunoregulation and prolongs graft survival following fully MHC mismatched transplantation in vivo. We suggest that these observations identify DEPTOR as a critical upstream intracellular modulator of CD4+ T cell activation as well as the phenotypic and functional outcome of the alloimmune response. Our objectives in this R01 are to further evaluate these observations using novel transgenic mice, and 1), define the select function of DEPTOR in CD4+ T effector and regulatory subsets in vivo, and 2), evaluate the consequences of CD4+ T cell DEPTOR expression in models of transplant rejection. We will test the hypothesis that DEPTOR is a cell intrinsic molecule that modulates CD4+ T effector cell activation and augments CD4+ T regulatory cell function to enhance immunoregulation and promote long-term graft survival. We propose two specific aims in which we will: 1), determine the consequences and mechanism of function of cell intrinsic DEPTOR in CD4+ T cell subsets, and 2), determine the function of CD4+ T cell DEPTOR in long-term allograft survival. Collectively, these innovative studies will have broad scientific and biological implications of great significance and relevance to transplantation immunobiology.

项目概要/摘要 同种异体移植排斥的特点是效应 CD4+ T 细胞响应供体抗原而激活，并且 对移植物的强烈的细胞和体液攻击。然而，CD4+ T 细胞内存在多种细胞内信号 同时作用增强 CD4+Foxp3+ T 调节细胞的扩增和功能 共同作用来控制同种免疫反应。此外，这个过程的效力 免疫调节可预防和抑制同种免疫 T 效应细胞的激活和排斥。重要的是， 最近的进展表明 CD4+Foxp3+ T 细胞的分化和功能受到 mTOR（特别是 mTORC1）的细胞内在活性。但对于监管的情况却知之甚少 同种异体反应性 CD4+ T 细胞效应细胞内的细胞内 mTOR 信号传导，或其相对活性如何 在 Foxp3+ 子集中进行调制，或者是否可以利用调制信号来增强 病理状态下的生理性 Treg 活性可预防疾病，包括慢性病的发展 同种异体移植排斥反应。 DEPTOR 是最近发现的一种细胞内因子，可调节 mTOR 诱导的 高度增殖的癌细胞中的信号反应，最近观察到它发挥作用 在包括血管内皮细胞在内的正常细胞类型中。在初步研究中，我们发现 DEPTOR 是 在未激活的 CD4+ T 细胞中高水平表达，并且进一步，其表达在 细胞激活。此外，我们发现 DEPTOR 的强制过度表达可调节 CD4+ T 细胞 完全 MHC 后体外激活反应，促进免疫调节并延长移植物存活 体内移植不匹配。我们认为这些观察结果表明 DEPTOR 是一个关键的 CD4+ T 细胞激活以及表型和功能结果的上游细胞内调节剂 的同种免疫反应。我们在此 R01 中的目标是使用以下方法进一步评估这些观察结果： 新型转基因小鼠，1) 定义了 DEPTOR 在 CD4+ T 效应子和调节中的选择功能 体内子集，2) 评估 CD4+ T 细胞 DEPTOR 表达在模型中的后果 移植排斥反应。我们将检验 DEPTOR 是一种调节细胞内在分子的假设 CD4+ T 效应细胞激活并增强 CD4+ T 调节细胞功能以增强免疫调节 并促进移植物的长期成活。我们提出两个具体目标，其中我们将： 1)、确定 CD4+ T 细胞亚群中细胞内在 DEPTOR 的功能后果和机制，以及 2)、 确定 CD4+ T 细胞 DEPTOR 在长期同种异体移植物存活中的功能。总的来说，这些创新 研究将产生广泛的科学和生物学意义，具有重大意义和相关性 移植免疫生物学。

项目成果

DEPTOR modulates activation responses in CD4+ T cells and enhances immunoregulation following transplantation.

DEPTOR 调节 CD4 T 细胞的激活反应并增强移植后的免疫调节。

• DOI: 10.1111/ajt.14995
• 发表时间: 2019
• 期刊: American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons
• 作者: Wedel,Johannes;Bruneau,Sarah;Liu,Kaifeng;Kong,SekWon;Sage,PeterT;Sabatini,DavidM;Laplante,Mathieu;Briscoe,DavidM
• 通讯作者: Briscoe,DavidM