Regulation of CD4 T cell tolerance by the NR4A family of nuclear receptors

核受体 NR4A 家族对 CD4 T 细胞耐受性的调节

基本信息

项目摘要

Project Summary/Abstract This proposal’s long-term goal is to take advantage of the biology of the NR4A family of orphan nuclear hormone receptors to selectively manipulate antigen-specific T cell responses in immune-mediated diseases. NR4A members (NUR77, NURR1, and NOR1) are encoded by three genes (Nr4a1-3, respectively) that are rapidly induced by antigen (Ag) stimulation in lymphocytes. Although they are thought to function as ligand- independent, constitutively active transcription factors, small molecule agonist and antagonist ligands have been developed, rendering them druggable. We and others have shown that NR4A TF expression scales with the intensity of Ag stimulation, and are highly upregulated in thymocytes undergoing negative selection, in regulatory T cells (Tregs), as well as in self-reactive, anergic, or exhausted T cells. Due to an overlapping expression pattern and considerable structural homology in their DNA-binding domain, the NR4A TFs exhibit profound functional redundancy; thymic deletion of multiple - but not individual - NR4A family members (Nr4a1 and Nr4a3 >> Nr4a2, which is minimally expressed) results in severe Treg deficiency and a “scurfy-like” disease that phenocopies Foxp3-/- mice. Consequently, it has not been possible previously to unmask additional redundant functions of this family during thymic selection and in conventional mature CD4 T cells (Tconv). This represents a major gap in our knowledge that limits full therapeutic exploitation of these factors. Recently, we took advantage of both conditional genetic and bone marrow chimera strategies in order to preserve Treg homeostasis. Unexpectedly, mixed chimeras harboring both WT and Nr4a1-/- Nr4a3-/- (DKO) bone marrow rapidly develop anti-nuclear autoantibodies (ANAs) and a systemic inflammatory disease despite a replete Treg compartment of largely WT origin. This disease differs qualitatively from that seen in germline DKO mice with Treg-deficiency, and is B cell-extrinsic. We show that negative selection of DKO thymocytes is profoundly impaired in a cell-intrinsic manner. Consistent with escape of self-reactive T cells into the periphery, DKO CD4 Tconv cells expressing phenotypic and transcriptional markers of anergy accumulate in these chimeras. However, these self-reactive DKO cells nevertheless exhibit exaggerated proliferation and IL-2 production, suggesting that functional anergy is defective. We therefore hypothesize that the NR4A family play cell-intrinsic, but redundant, roles in both central and peripheral CD4 T cell tolerance. To test this hypothesis: In our first aim, we propose to define the role of the NR4A family in thymic negative selection in the face of both ubiquitous and tissue-restricted antigens, and to define the transcriptional targets that contribute to this function. In our second aim, we propose to isolate NR4A contributions to peripheral T cell tolerance, and to canonical features of mature CD4 T cell anergy - including impaired signal transduction, cytokine production, and proliferation. We will use both bulk and single cell genomic approaches to define the mechanism by which the NR4A family regulates the transcriptome and epigenetic profile of naïve and tolerant CD4 T cells.
项目总结/文摘

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

JULIE ZIKHERMAN其他文献

JULIE ZIKHERMAN的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('JULIE ZIKHERMAN', 18)}}的其他基金

Regulation of CD4 T cell tolerance by the NR4A family of nuclear receptors
核受体 NR4A 家族对 CD4 T 细胞耐受性的调节
  • 批准号:
    10707222
  • 财政年份:
    2022
  • 资助金额:
    $ 60.31万
  • 项目类别:
Nuclear Receptors in B Cell Tolerance and Humoral Immune Responses
B 细胞耐受和体液免疫反应中的核受体
  • 批准号:
    10626756
  • 财政年份:
    2020
  • 资助金额:
    $ 60.31万
  • 项目类别:
Nuclear Receptors in B Cell Tolerance and Humoral Immune Responses
B 细胞耐受和体液免疫反应中的核受体
  • 批准号:
    10410354
  • 财政年份:
    2020
  • 资助金额:
    $ 60.31万
  • 项目类别:
Nuclear Receptors in B Cell Tolerance and Humoral Immune Responses
B 细胞耐受和体液免疫反应中的核受体
  • 批准号:
    10192648
  • 财政年份:
    2020
  • 资助金额:
    $ 60.31万
  • 项目类别:
Dissecting unique functions of IgM and IgD BCRs in tolerance and autoimmunity
剖析 IgM 和 IgD BCR 在耐受和自身免疫中的独特功能
  • 批准号:
    9193713
  • 财政年份:
    2016
  • 资助金额:
    $ 60.31万
  • 项目类别:
Dissecting unique functions of IgM and IgD BCRs in tolerance and autoimmunity
剖析 IgM 和 IgD BCR 在耐受和自身免疫中的独特功能
  • 批准号:
    9899730
  • 财政年份:
    2016
  • 资助金额:
    $ 60.31万
  • 项目类别:
Dissecting unique functions of IgM and IgD BCRs in tolerance and autoimmunity
剖析 IgM 和 IgD BCR 在耐受和自身免疫中的独特功能
  • 批准号:
    9479603
  • 财政年份:
    2016
  • 资助金额:
    $ 60.31万
  • 项目类别:
Titrating CD45 expression in mice to study development of T cell tolerance
滴定小鼠 CD45 表达以研究 T 细胞耐受的发展
  • 批准号:
    8098871
  • 财政年份:
    2010
  • 资助金额:
    $ 60.31万
  • 项目类别:
Titrating CD45 expression in mice to study development of T cell tolerance
滴定小鼠 CD45 表达以研究 T 细胞耐受的发展
  • 批准号:
    8701864
  • 财政年份:
    2010
  • 资助金额:
    $ 60.31万
  • 项目类别:
Titrating CD45 expression in mice to study development of T cell tolerance
滴定小鼠 CD45 表达以研究 T 细胞耐受的发展
  • 批准号:
    7952505
  • 财政年份:
    2010
  • 资助金额:
    $ 60.31万
  • 项目类别:

相似国自然基金

Agonist-GPR119-Gs复合物的结构生物学研究
  • 批准号:
    32000851
  • 批准年份:
    2020
  • 资助金额:
    24.0 万元
  • 项目类别:
    青年科学基金项目

相似海外基金

S1PR1 agonistによる脳血液関門制御を介した脳梗塞の新規治療法開発
S1PR1激动剂调节血脑屏障治疗脑梗塞新方法的开发
  • 批准号:
    24K12256
  • 财政年份:
    2024
  • 资助金额:
    $ 60.31万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
AHR agonistによるSLE皮疹の新たな治療薬の開発
使用 AHR 激动剂开发治疗 SLE 皮疹的新疗法
  • 批准号:
    24K19176
  • 财政年份:
    2024
  • 资助金额:
    $ 60.31万
  • 项目类别:
    Grant-in-Aid for Early-Career Scientists
Evaluation of a specific LXR/PPAR agonist for treatment of Alzheimer's disease
特定 LXR/PPAR 激动剂治疗阿尔茨海默病的评估
  • 批准号:
    10578068
  • 财政年份:
    2023
  • 资助金额:
    $ 60.31万
  • 项目类别:
AUGMENTING THE QUALITY AND DURATION OF THE IMMUNE RESPONSE WITH A NOVEL TLR2 AGONIST-ALUMINUM COMBINATION ADJUVANT
使用新型 TLR2 激动剂-铝组合佐剂增强免疫反应的质量和持续时间
  • 批准号:
    10933287
  • 财政年份:
    2023
  • 资助金额:
    $ 60.31万
  • 项目类别:
Targeting breast cancer microenvironment with small molecule agonist of relaxin receptor
用松弛素受体小分子激动剂靶向乳腺癌微环境
  • 批准号:
    10650593
  • 财政年份:
    2023
  • 资助金额:
    $ 60.31万
  • 项目类别:
AMPKa agonist in attenuating CPT1A inhibition and alcoholic chronic pancreatitis
AMPKa 激动剂减轻 CPT1A 抑制和酒精性慢性胰腺炎
  • 批准号:
    10649275
  • 财政年份:
    2023
  • 资助金额:
    $ 60.31万
  • 项目类别:
Investigating mechanisms underpinning outcomes in people on opioid agonist treatment for OUD: Disentangling sleep and circadian rhythm influences on craving and emotion regulation
研究阿片类激动剂治疗 OUD 患者结果的机制:解开睡眠和昼夜节律对渴望和情绪调节的影响
  • 批准号:
    10784209
  • 财政年份:
    2023
  • 资助金额:
    $ 60.31万
  • 项目类别:
A randomized double-blind placebo controlled Phase 1 SAD study in male and female healthy volunteers to assess safety, pharmacokinetics, and transient biomarker changes by the ABCA1 agonist CS6253
在男性和女性健康志愿者中进行的一项随机双盲安慰剂对照 1 期 SAD 研究,旨在评估 ABCA1 激动剂 CS6253 的安全性、药代动力学和短暂生物标志物变化
  • 批准号:
    10734158
  • 财政年份:
    2023
  • 资助金额:
    $ 60.31万
  • 项目类别:
A novel nanobody-based agonist-redirected checkpoint (ARC) molecule, aPD1-Fc-OX40L, for cancer immunotherapy
一种基于纳米抗体的新型激动剂重定向检查点 (ARC) 分子 aPD1-Fc-OX40L,用于癌症免疫治疗
  • 批准号:
    10580259
  • 财政年份:
    2023
  • 资助金额:
    $ 60.31万
  • 项目类别:
Identification and characterization of a plant growth promoter from wild plants: is this a novel plant hormone agonist?
野生植物中植物生长促进剂的鉴定和表征:这是一种新型植物激素激动剂吗?
  • 批准号:
    23K05057
  • 财政年份:
    2023
  • 资助金额:
    $ 60.31万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了