Control of Regulatory T Cell Function by Toll-Like Receptor 7
Toll 样受体 7 对调节性 T 细胞功能的控制
基本信息
- 批准号:10304769
- 负责人:
- 金额:$ 56.43万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-07-01 至 2026-06-30
- 项目状态:未结题
- 来源:
- 关键词:AdoptedAdoptive TransferAgonistAllelesAmphiregulinAreaAutoantigensBiologyBleomycinCell TherapyCell physiologyCellsClinicalComputational BiologyCuesCytokine ReceptorsDataDetectionEGF geneFamilyFamily memberFoundationsGene ExpressionGene Expression ProfileGenesHeterogeneityHomeostasisHumanImmuneImmune ToleranceImpairmentIn VitroInfectionInflammationInfluenzaInjuryInterleukin-1Interleukin-18Knockout MiceLigandsLinkLungLung infectionsMaintenanceMediatingMetabolismModalityModelingMolecular ChaperonesMusMuscleMutant Strains MiceNatural ImmunityNucleic AcidsPopulationRNARegulatory T-LymphocyteReporterRoleSignal PathwaySignal TransductionTLR7 geneTestingTherapeuticTissuesTreg therapyViralWorkadaptive immunitybasecytokinegene repairimprovedinterestlung injurylung repairmembermutantnext generation sequencingpathogenreceptorrepair functionrepairedresponsesensorsingle-cell RNA sequencingtherapeutic evaluationtissue repairviral RNA
项目摘要
ABSTRACT
Regulatory T cells (Tregs) are critical for the maintenance of immunological tolerance but more recently their
importance in regulating other aspects of tissue homeostasis has been an area of intense interest. Most
relevant to this application are populations of tissue-resident Tregs that accumulate upon injury and facilitate
tissue repair by producing factors such as the EGF family member amphiregulin (Areg). These repair functions
are distinct from the suppressive function classically attributed to Tregs, but the signals that instruct Tregs to
adopt these distinct functional modalities have not been well defined. The IL-1 family cytokines IL-18 and IL-33
are involved at some level, at least in certain tissues, but it remains unclear whether these cytokines act as the
key initial determinants of Treg function.
This proposal will test the hypothesis that Toll-like receptor 7 (TLR7) signaling in Tregs is a key determinant of
Treg tissue repair function. We propose that TLR7 enables Tregs to sense pathogen-derived nucleic acids as
well as self RNA released from damaged host tissues. Our hypothesis is based on our analysis of a panel of
TLR reporter mice, which revealed that only TLR7 is expressed on Tregs, as well as strong preliminary data
demonstrating that TLR7 can induce expression of the signature tissue repair gene, Areg, in both murine and
human Tregs. Using newly generated mice with Treg-specific deletion of TLR7, we will examine the
importance of TLR7 signaling in Tregs during lung damage (Aim 1). Single-cell RNA sequencing will identify
which subsets of lung Tregs are controlled by TLR7 and will define TLR7-dependent genes in Tregs. We will
also investigate the importance of IL18R and IL33R signaling in Tregs, using mice with Treg-specific deletion
of these receptors, and will determine the extent to which TLR7, IL18R, and IL33R regulate distinct aspects of
Treg expansion and/or differentiation in response to diverse lung damaging agents (Aim 2). Finally, we will
build on our recent work that identified a mechanism by which the TLR chaperone Unc93b1 specifically
dampens TLR7 signaling. Using Tregs from mice with mutant Unc93b1 that have enhanced TLR7 signaling,
we will test whether adoptive therapy of Tregs with enhanced TLR7 responses to viral and self RNA can
mediate more effective repair of lung damage (Aim 3).
Altogether, these studies will define the signals that control Treg tissue repair functions and test the therapeutic
potential of amplifying these signals in the context of lung damage, a key first step toward therapeutic
manipulation of Treg function for clinical benefit.
摘要
调节性T细胞(Tcells)对于维持免疫耐受性至关重要,但最近它们的免疫耐受性降低。
在调节组织稳态的其它方面中的重要性已经成为人们强烈关注的领域。最
与该应用相关的是在损伤时积累的组织驻留TdR群体,
组织修复通过产生因子,如EGF家族成员双调蛋白(Areg)。这些修复功能
与传统上归因于TdR的抑制功能不同,但是指示TdR
采用这些不同的职能模式尚未得到很好的界定。IL-1家族细胞因子IL-18和IL-33
至少在某些组织中,这些细胞因子在某种程度上参与其中,但目前尚不清楚这些细胞因子是否作为
Treg功能的关键初始决定因素。
这项提议将检验Toll样受体7(TLR7)信号转导是Toll样受体表达的关键决定因素这一假设。
Treg组织修复功能。我们提出TLR7使TcR能够感测病原体衍生的核酸,
以及从受损的宿主组织中释放的自身RNA。我们的假设是基于我们对一组
TLR报告小鼠,其揭示了只有TLR7在TcB上表达,以及强有力的初步数据
这表明TLR7可以在小鼠和小鼠中诱导标志性组织修复基因Areg的表达,
人的舌头。使用新产生的Treg特异性TLR7缺失的小鼠,我们将检查
TLR7信号传导在肺损伤过程中的重要性(目的1)。单细胞RNA测序将确定
肺TCLs的哪些亚群受TLR7控制并将定义TCLs中的TLR7依赖性基因。我们将
我还使用Treg特异性缺失的小鼠研究了IL 18 R和IL 33 R信号在Treg中的重要性
这些受体,并将确定TLR7,IL18R和IL33R调节这些受体的不同方面的程度。
响应于不同肺损伤剂的Treg扩增和/或分化(目的2)。最后我们将
基于我们最近的工作,确定了TLR伴侣蛋白Unc93b1特异性地
抑制TLR7信号传导。使用来自具有增强的TLR7信号传导的突变体Unc93b1的小鼠的Tclase,
我们将测试对病毒和自身RNA具有增强的TLR7应答的TcR的过继治疗是否可以
介导更有效的肺损伤修复(目标3)。
总之,这些研究将定义控制Treg组织修复功能的信号,并测试治疗性免疫缺陷的方法。
在肺损伤的背景下放大这些信号的潜力,这是治疗的关键第一步。
操纵Treg功能以获得临床益处。
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 }}
Gregory M Barton其他文献
Toll signaling: RIPping off the TNF pathway
收费信号:利用肿瘤坏死因子通路
- DOI:
10.1038/ni0504-472 - 发表时间:
2004-05-01 - 期刊:
- 影响因子:27.600
- 作者:
Gregory M Barton;Ruslan Medzhitov - 通讯作者:
Ruslan Medzhitov
The path ahead for understanding Toll-like receptor-driven systemic autoimmunity
理解 Toll 样受体驱动的全身性自身免疫的未来之路
- DOI:
10.1016/j.coi.2024.102482 - 发表时间:
2024-12-01 - 期刊:
- 影响因子:5.800
- 作者:
Jessica A Hamerman;Gregory M Barton - 通讯作者:
Gregory M Barton
Unfolding new roles for XBP1 in immunity
揭示 XBP1 在免疫中的新作用
- DOI:
10.1038/ni0510-365 - 发表时间:
2010-05-01 - 期刊:
- 影响因子:27.600
- 作者:
Alex Engel;Gregory M Barton - 通讯作者:
Gregory M Barton
Gregory M Barton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('Gregory M Barton', 18)}}的其他基金
The Signal Transduction in the Immune System Conference
免疫系统会议中的信号转导
- 批准号:
10683527 - 财政年份:2023
- 资助金额:
$ 56.43万 - 项目类别:
Control of Regulatory T Cell Function by Toll-Like Receptor 7
Toll 样受体 7 对调节性 T 细胞功能的控制
- 批准号:
10438923 - 财政年份:2021
- 资助金额:
$ 56.43万 - 项目类别:
Control of Regulatory T Cell Function by Toll-Like Receptor 7
Toll 样受体 7 对调节性 T 细胞功能的控制
- 批准号:
10650735 - 财政年份:2021
- 资助金额:
$ 56.43万 - 项目类别:
The influence of maternal antibodies on neonatal intestinal immunity
母源抗体对新生儿肠道免疫的影响
- 批准号:
9677877 - 财政年份:2018
- 资助金额:
$ 56.43万 - 项目类别:
The influence of maternal antibodies on neonatal intestinal immunity
母源抗体对新生儿肠道免疫的影响
- 批准号:
9790941 - 财政年份:2018
- 资助金额:
$ 56.43万 - 项目类别:
相似海外基金
Time to ATTAC: Adoptive Transfer of T cells Against gp100+ Cells to treat LAM
ATTAC 时间:针对 gp100 细胞的 T 细胞过继转移来治疗 LAM
- 批准号:
10682121 - 财政年份:2023
- 资助金额:
$ 56.43万 - 项目类别:
Phase I clinical trial of adoptive transfer of autologous folate receptor-alpha redirected CAR T cells for ovarian cancer
自体叶酸受体-α重定向CAR T细胞过继转移治疗卵巢癌的I期临床试验
- 批准号:
10576370 - 财政年份:2022
- 资助金额:
$ 56.43万 - 项目类别:
Phase I clinical trial of adoptive transfer of autologous folate receptor-alpha redirected CAR T cells for ovarian cancer
自体叶酸受体-α重定向CAR T细胞过继转移治疗卵巢癌的I期临床试验
- 批准号:
10387023 - 财政年份:2022
- 资助金额:
$ 56.43万 - 项目类别:
Determining mechanisms of enhanced antitumor efficacy of four-day expanded Th17 cells for adoptive transfer
确定用于过继转移的四天扩增 Th17 细胞增强抗肿瘤功效的机制
- 批准号:
10248409 - 财政年份:2019
- 资助金额:
$ 56.43万 - 项目类别:
A phase I clinical study of adoptive transfer of regulatory T cells (Tregs) and low-dose interleukin-2 (IL-2) for the treatment of chronic graft-versus-host disease (GVHD): gene-marking to inform rational combination therapy
调节性 T 细胞 (Treg) 和低剂量白细胞介素 2 (IL-2) 过继转移治疗慢性移植物抗宿主病 (GVHD) 的 I 期临床研究:基因标记为合理的联合治疗提供信息
- 批准号:
nhmrc : GNT1163111 - 财政年份:2019
- 资助金额:
$ 56.43万 - 项目类别:
Project Grants
Determining mechanisms of enhanced antitumor efficacy of four-day expanded Th17 cells for adoptive transfer
确定用于过继转移的四天扩增 Th17 细胞增强抗肿瘤功效的机制
- 批准号:
10462684 - 财政年份:2019
- 资助金额:
$ 56.43万 - 项目类别:
Gene edited lymphoid progenitors for adoptive transfer as a treatment of primary immunodeficiency
基因编辑的淋巴祖细胞用于过继转移作为原发性免疫缺陷的治疗
- 批准号:
398018062 - 财政年份:2018
- 资助金额:
$ 56.43万 - 项目类别:
Research Grants
Overcoming immune suppression in cancer by targeting PSGL-1 in T cells used for adoptive transfer
通过靶向用于过继转移的 T 细胞中的 PSGL-1 克服癌症中的免疫抑制
- 批准号:
9308643 - 财政年份:2017
- 资助金额:
$ 56.43万 - 项目类别:
Overcoming immune suppression in cancer by targeting PSGL-1 in T cells used for adoptive transfer
通过靶向用于过继转移的 T 细胞中的 PSGL-1 克服癌症中的免疫抑制
- 批准号:
9447149 - 财政年份:2017
- 资助金额:
$ 56.43万 - 项目类别:
Targeting Cancer miRNAs by Adoptive Transfer of Programmed B Lymphocytes
通过程序化 B 淋巴细胞的过继转移靶向癌症 miRNA
- 批准号:
8893915 - 财政年份:2014
- 资助金额:
$ 56.43万 - 项目类别: