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
基本信息
- 批准号:10302288
- 负责人:
- 金额:$ 57.53万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:AcuteAddressAllograftingAntigensAreaBiologicalBiological Response Modifier TherapyBiologyCD4 Positive T LymphocytesCell CommunicationCell Differentiation processCell physiologyCellsCellular Metabolic ProcessChronicDevelopmentDiseaseEragrostisExcisionFOXP3 geneFRAP1 geneFundingGraft RejectionGraft SurvivalImmunobiologyImmunosuppressionIn VitroIndividualIntrinsic factorKnock-in MouseKnockout MiceLifeLinkLiteratureMetabolic PathwayMetabolismModelingNormal CellOrgan TransplantationOutcomePathologicPharmacologyPhenotypePhysiologicalPreventionProcessRegulationRegulatory T-LymphocyteResearchResearch ProposalsRoleSavingsSignal TransductionSirolimusT cell differentiationT-Cell ActivationT-Lymphocyte SubsetsTestingTherapeuticTransgenic MiceTransgenic OrganismsTransplantationUbiquitinationVascular Endothelial Cellallograft rejectioncancer cellcell typeclinically relevantcohesioneffector T cellend-stage organ failurefunctional outcomesgenetic regulatory proteinimmunoregulationin vivoin vivo ModelinhibitorinnovationinsightisoimmunitymTOR Inhibitornoveloverexpressionpreventresponsesmall moleculetransplant model
项目摘要
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
期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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:
- 影响因子:0
- 作者:Wedel,Johannes;Bruneau,Sarah;Liu,Kaifeng;Kong,SekWon;Sage,PeterT;Sabatini,DavidM;Laplante,Mathieu;Briscoe,DavidM
- 通讯作者:Briscoe,DavidM
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David M. Briscoe其他文献
Outcome of renal transplantation in children less than two years of age
- DOI:
10.1038/ki.1992.331 - 发表时间:
1992-09-01 - 期刊:
- 影响因子:
- 作者:
David M. Briscoe;Melanie S. Kim;Craig Lillehei;Angelo J. Eraklis;Raphael H. Levey;William E. Harmon - 通讯作者:
William E. Harmon
Risk factors for mortality in infants and young children on dialysis.
透析婴幼儿死亡的危险因素。
- DOI:
- 发表时间:
2001 - 期刊:
- 影响因子:13.2
- 作者:
Ellen G. Wood;Matthew Hand;David M. Briscoe;Lynn A. Donaldson;Verna Yiu;Frances L. Harley;B. Warady;Eileen N. Ellis - 通讯作者:
Eileen N. Ellis
David M. Briscoe的其他文献
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{{ truncateString('David M. Briscoe', 18)}}的其他基金
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:
10062851 - 财政年份:2017
- 资助金额:
$ 57.53万 - 项目类别:
Function 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:
8785808 - 财政年份:2014
- 资助金额:
$ 57.53万 - 项目类别:
Vascular Endothelial Growth Factor Receptor Interactions and Allograft Rejection
血管内皮生长因子受体相互作用和同种异体移植排斥
- 批准号:
8239118 - 财政年份:2011
- 资助金额:
$ 57.53万 - 项目类别:
Role of T cell Specific Adaptor Protein in Alloimmunity
T 细胞特异性衔接蛋白在同种免疫中的作用
- 批准号:
8190975 - 财政年份:2011
- 资助金额:
$ 57.53万 - 项目类别:
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