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.

项目摘要/摘要 同种异体移植排斥的特征是效应子CD4+ T细胞激活供体抗原和A 对移植物的强烈细胞和体液攻击。但是，CD4+ T细胞中的多个细胞内信号 共同运行以增强CD4+ FOXP3+ T调节细胞的扩展和功能 共同用于控制同种免疫反应。此外，这一过程的效力 免疫调节可防止并限制同育T效应细胞的激活和排斥。重要的是， 最近的进步表明，CD4+ FOXP3+ T细胞分化和功能受到负面调节 MTOR和MTORC1的细胞固有活性。但是，对调节的规定知之甚少 同种反应性CD4+ T细胞效应子内的细胞内MTOR信号传导，或其相对活性如何 在Foxp3+子集中调制，或是否可以利用调制信号来增加 病理状态中的生理Treg活性预防疾病，包括慢性的发展 同种异体移植排斥。 Deptor是最近发现的细胞内在因素，可调节MTOR诱导的 高度增殖性癌细胞中的信号反应，最近观察到它起作用 在正常细胞类型中，包括血管内皮细胞。在初步研究中，我们发现Deptor是 在未激活的CD4+ T细胞中以高水平表达，进一步表明其表达在 细胞激活。此外，我们发现被迫过表达Deptor会调节CD4+ T细胞 在体外激活反应，促进免疫调节并延长完全MHC后的移植物存活率 体内不匹配的移植。我们建议这些观察结果将神人视为关键 CD4+ T细胞激活的上游细胞内调节剂以及表型和功能结果 同种免疫反应。我们在R01中的目标是进一步评估这些观察结果 新颖的转基因小鼠和1）定义了CD4+ T效应子和调节性的Deptor的选择功能 体内子集和2）在模型中评估CD4+ T细胞源表达的后果 移植排斥。我们将检验以下假设：Deptor是调节的细胞固有分子 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 并促进长期的移植生存。我们提出了两个我们将要的具体目标：1），确定 CD4+ T细胞子集中细胞固有神经源功能功能的后果和机制，2）， 确定CD4+ T细胞在长期同种异体移植存活中的功能。总的来说，这些创新 研究将具有广泛的科学和生物学意义，具有与 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