CD40-Induced TCR Revision: A Mechanism for Autoimmunity
CD40 诱导的 TCR 修正:自身免疫机制
基本信息
- 批准号:8113290
- 负责人:
- 金额:$ 27.29万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2007
- 资助国家:美国
- 起止时间:2007-08-01 至 2013-04-30
- 项目状态:已结题
- 来源:
- 关键词:AddressAffectAgeAntigensAutoimmune DiseasesAutoimmune ProcessAutoimmunityBiological AssayCD40 LigandCellsDevelopmentDiabetes MellitusDiseaseDisease modelEventGenerationsGenetic RecombinationGoalsGrantHaplotypesHumanHyperglycemiaIn VitroInbred NOD MiceInsulin-Dependent Diabetes MellitusKineticsLaboratoriesLightManuscriptsMediatingMemoryModelingMouse StrainsMusNon-Insulin-Dependent Diabetes MellitusOvalbuminPancreasPeripheralPhenotypePlayPopulationPreventionProcessReceptor CellRiskRoleSourceSpecificitySystemT cell responseT-Cell ActivationT-Cell Immunologic SpecificityT-Cell ReceptorT-LymphocyteT-Lymphocyte SubsetsTNFRSF5 geneTNFSF5 geneTestingTherapeuticTransgenic MiceTranslatingdesignhuman diseasein vivoin vivo Modelinsulin dependent diabetes mellitus onsetnon-diabeticpreventreceptor expressionresearch studyresponse
项目摘要
DESCRIPTION (provided by applicant): The goals of this application are to address the development of CD40+ T cells, the role that CD40 plays in T cell receptor (TCR) revision and how induced TCR revision impacts autoimmunity. CD40 has a direct role in autoimmune diseases including type 1 diabetes (T1D). We discovered that a unique subset of effector T cells, described as CD4loCD40+, are highly pathogenic in T1 D. CD40 is present on diabetogenic T cell clones and primary CD4loCD40+ T cells expand concurrently with insulitis in NOD mice. Importantly, CD4loCD40+ T cells readily transfer T1D to NOD.scid recipients. Mechanistically, CD40 induces the RAG1/RAG2 recombination machinery in T cells. Following that induction, TCR revision, induced alteration of TCR expression, occurs. Some revised primary T cells were found to be highly pathogenic. However, CD40 induced TCR revision could serve as a functional tolerance mechanism of established diabetogenic T cell clones. Specifically, CD40 engaging the diabetogenic T cell clone BDC2.5 severely ablated disease transfer ability of the clone. We showed that blocking CD40 - CD154 (the ligand for CD40) interaction in NOD mice at 3-weeks of age prevents not only T1D onset, but prevents expansion of CD4loCD40+, autoaggressive cells. In this application we will explore how CD40 affects the unique T cell population. Our hypothesis is that TCR revision directly impacts T cell tolerance. Specific Aim #1: Do CD4loCD40+ T cells comprise a unique T cell subset or represent a transient activation state within T cells? If CD40 is induced on T cells are there differences in those T cells compared to the intrinsic CD40 T cell subset? We plan experiments to address this central concern. Specific Aim #2: How does CD40 engagement affect TCR revision in CD4loCD40+ T cells? Are there differences in response to CD40 engagement between autoimmune and non-autoimmune conditions? We will explore RAG1 and RAG2 induction, kinetics of TCR revision and how different sources of CD154 in autoimmune versus non-autoimmune mice affect this process. Specific Aim #3: How does CD40 engagement affect T cell antigen specificity? We will explore how induced TCR revision affects T cell antigen specificity using in vitro and in vivo models. These proposed studies address not only the development of potential autoaggressive T cells but will provide important information as to whether induced TCR revision is pathogenic or tolerogenic.
描述(由申请人提供):本申请的目标是解决 CD40+ T 细胞的发育、CD40 在 T 细胞受体 (TCR) 修正中的作用以及诱导的 TCR 修正如何影响自身免疫。 CD40 在包括 1 型糖尿病 (T1D) 在内的自身免疫性疾病中具有直接作用。我们发现效应 T 细胞的一个独特子集(被描述为 CD4loCD40+)在 T1 D 中具有高致病性。CD40 存在于致糖尿病 T 细胞克隆上,并且原代 CD4loCD40+ T 细胞在 NOD 小鼠中与胰岛炎同时扩增。重要的是,CD4loCD40+T细胞很容易将T1D转移给NOD.scid受体。从机制上讲,CD40 诱导 T 细胞中的 RAG1/RAG2 重组机制。诱导后,TCR 修正(TCR 表达的诱导改变)发生。一些修改后的原代 T 细胞被发现具有高致病性。然而,CD40 诱导的 TCR 修正可以作为已建立的糖尿病 T 细胞克隆的功能耐受机制。具体来说,CD40 与致糖尿病 T 细胞克隆 BDC2.5 结合,严重削弱了该克隆的疾病转移能力。我们发现,在 3 周龄的 NOD 小鼠中阻断 CD40 - CD154(CD40 的配体)相互作用不仅可以防止 T1D 发作,还可以防止 CD4loCD40+ 自身攻击性细胞的扩增。在此应用中,我们将探讨 CD40 如何影响独特的 T 细胞群。我们的假设是 TCR 修订直接影响 T 细胞耐受性。具体目标#1:CD4loCD40+ T 细胞是否包含独特的 T 细胞亚群或代表 T 细胞内的瞬时激活状态?如果 CD40 在 T 细胞上被诱导,这些 T 细胞与内在的 CD40 T 细胞亚群相比是否存在差异?我们计划进行实验来解决这个核心问题。具体目标#2:CD40 参与如何影响 CD4loCD40+ T 细胞中的 TCR 修正?自身免疫性疾病和非自身免疫性疾病对 CD40 参与的反应是否存在差异?我们将探讨 RAG1 和 RAG2 的诱导、TCR 修正的动力学以及自身免疫小鼠与非自身免疫小鼠中不同来源的 CD154 如何影响这一过程。具体目标#3:CD40 结合如何影响 T 细胞抗原特异性?我们将使用体外和体内模型探索诱导 TCR 修正如何影响 T 细胞抗原特异性。这些拟议的研究不仅涉及潜在的自身攻击性 T 细胞的发育,还将提供关于诱导 TCR 修正是否致病或耐受的重要信息。
项目成果
期刊论文数量(7)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
An alternative role for Foxp3 as an effector T cell regulator controlled through CD40.
Foxp3 的另一个角色是通过 CD40 控制的效应 T 细胞调节剂。
- DOI:10.4049/jimmunol.1300625
- 发表时间:2013
- 期刊:
- 影响因子:0
- 作者:Vaitaitis,GiselaM;Carter,JessicaR;Waid,DanM;Olmstead,MichaelH;WagnerJr,DavidH
- 通讯作者:WagnerJr,DavidH
CD40 interacts directly with RAG1 and RAG2 in autoaggressive T cells and Fas prevents CD40-induced RAG expression.
- DOI:10.1038/cmi.2013.24
- 发表时间:2013-11
- 期刊:
- 影响因子:24.1
- 作者:
- 通讯作者:
Galectin-9 controls CD40 signaling through a Tim-3 independent mechanism and redirects the cytokine profile of pathogenic T cells in autoimmunity.
- DOI:10.1371/journal.pone.0038708
- 发表时间:2012
- 期刊:
- 影响因子:3.7
- 作者:Vaitaitis GM;Wagner DH Jr
- 通讯作者:Wagner DH Jr
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David H. Wagner其他文献
The co-evolution of our understanding of CD40 and inflammation
我们对 CD40 和炎症的理解的共同进化
- DOI:
- 发表时间:
2009 - 期刊:
- 影响因子:8.2
- 作者:
David H. Wagner - 通讯作者:
David H. Wagner
Of the multiple mechanisms leading to type 1 diabetes, T cell receptor revision may play a prominent role (is type 1 diabetes more than a single disease?)
在导致 1 型糖尿病的多种机制中,T 细胞受体修改可能发挥着重要作用(1 型糖尿病不仅仅是一种疾病吗?)
- DOI:
10.1111/cei.12819 - 发表时间:
2016 - 期刊:
- 影响因子:4.6
- 作者:
David H. Wagner - 通讯作者:
David H. Wagner
Errors in the Choice of Abdominal Wall Incisions and in Their Closure
- DOI:
10.1016/s0039-6109(16)35393-2 - 发表时间:
1958-02-01 - 期刊:
- 影响因子:
- 作者:
David H. Wagner - 通讯作者:
David H. Wagner
Arterial thrombosis in the newborn infant
- DOI:
10.1016/s0022-3476(50)80031-8 - 发表时间:
1950-08-01 - 期刊:
- 影响因子:
- 作者:
Harold D. Perlmutter;David H. Wagner - 通讯作者:
David H. Wagner
David H. Wagner的其他文献
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{{ truncateString('David H. Wagner', 18)}}的其他基金
Discovering the Mechanism of Action of a peptide drug, OPT101, that targets CD40 mediated inflammation in type 1 diabetes
发现肽药物 OPT101 的作用机制,该药物针对 1 型糖尿病中 CD40 介导的炎症
- 批准号:
10345075 - 财政年份:2022
- 资助金额:
$ 27.29万 - 项目类别:
Discovering the Mechanism of Action of a peptide drug, OPT101, that targets CD40 mediated inflammation in type 1 diabetes
发现肽药物 OPT101 的作用机制,该药物针对 1 型糖尿病中 CD40 介导的炎症
- 批准号:
10589075 - 财政年份:2022
- 资助金额:
$ 27.29万 - 项目类别:
A unique approach to control the CD40/CD154 inflammatory axis in type 1 diabetes
控制 1 型糖尿病 CD40/CD154 炎症轴的独特方法
- 批准号:
8508619 - 财政年份:2013
- 资助金额:
$ 27.29万 - 项目类别:
A unique approach to control the CD40/CD154 inflammatory axis in type 1 diabetes
控制 1 型糖尿病 CD40/CD154 炎症轴的独特方法
- 批准号:
8716665 - 财政年份:2013
- 资助金额:
$ 27.29万 - 项目类别:
CD40-Induced TCR Revision: A Mechanism for Autoimmunity
CD40 诱导的 TCR 修正:自身免疫机制
- 批准号:
8000721 - 财政年份:2010
- 资助金额:
$ 27.29万 - 项目类别:
CD40-Induced TCR Revision: A Mechanism for Autoimmunity
CD40 诱导的 TCR 修正:自身免疫机制
- 批准号:
7771490 - 财政年份:2007
- 资助金额:
$ 27.29万 - 项目类别:
CD40-Induced TCR Revision: A Mechanism for Autoimmunity
CD40 诱导的 TCR 修正:自身免疫机制
- 批准号:
7313568 - 财政年份:2007
- 资助金额:
$ 27.29万 - 项目类别:
CD40-Induced TCR Revision: A Mechanism for Autoimmunity
CD40 诱导的 TCR 修正:自身免疫机制
- 批准号:
7655274 - 财政年份:2007
- 资助金额:
$ 27.29万 - 项目类别:
CD40-Induced TCR Revision: A Mechanism for Autoimmunity
CD40 诱导的 TCR 修正:自身免疫机制
- 批准号:
7473258 - 财政年份:2007
- 资助金额:
$ 27.29万 - 项目类别:
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