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 同种异体移植排斥反应的特征是效应者CD4+T细胞对供者抗原和AFP的反应 对移植物进行强烈的细胞和体液攻击。然而，CD4+T细胞内的多个细胞内信号 协同作用以增强CD4+Foxp3+T调节细胞的扩增和功能 共同控制同种异体免疫反应。此外，这一过程的效力 免疫调节预防和抑制同种异体免疫T效应细胞的激活和排斥。重要的是 最近的研究表明，CD4+Foxp3+T细胞的分化和功能受 MTOR和特异性mTORC1的细胞内源性活性。然而，人们对此知之甚少。 同种异体反应性CD4+T细胞效应器内的mTOR信号，或其相对活性如何 在Foxp3+子集中调制，或者是否有可能利用调制信号来增强 生理性Treg活动在病理状态下预防疾病，包括发展为慢性 同种异体排斥反应。DEPTOR是新近发现的一种调节mTOR诱导的细胞内在因子 高增殖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细胞中高水平表达，并且进一步地，其表达在 细胞激活。此外，我们还发现，DEPTOR的强制过表达对CD4+T细胞有调节作用 完全MHC后的体外激活反应，促进免疫调节和延长移植物存活 体内不相合移植。我们认为这些观察结果表明DEPTOR是一个关键的 CD4+T细胞激活的上游细胞内调节剂及其表型和功能结果 同种异体免疫反应。我们在R01中的目标是进一步评估这些观察结果，使用 新的转基因小鼠，以及1)，确定了DEPTOR在CD4+T效应和调节中的选择功能 体内亚群，以及2)，评估CD4+T细胞DEPTOR表达在模型中的后果。 移植排斥反应。我们将检验这样一个假设，即DEPTOR是一种细胞固有分子，它调节 激活和增强CD4+T调节细胞功能以加强免疫调节 并促进移植物的长期存活。我们提出了两个具体目标，我们将在其中：1)确定 CD4+T细胞亚群中细胞内源性DEPTOR功能的后果和机制，以及2)， 确定CD4+T细胞递减因子在移植物长期存活中的作用。总体而言，这些创新的 研究将具有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