Specification of Treg cells: learning from FoxP3 deficiencies
Treg 细胞的规范:从 FoxP3 缺陷中学习
基本信息
- 批准号:10652618
- 负责人:
- 金额:$ 55.6万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-06-27 至 2027-05-31
- 项目状态:未结题
- 来源:
- 关键词:3-DimensionalATAC-seqAffectAlanineAppearanceArchitectureAustraliaAutoimmuneAutoimmune DiseasesAutoimmunityBackBostonCD4 Positive T LymphocytesCell NucleusCell physiologyCellsCharacteristicsChromatinChromatin StructureClinicalClustered Regularly Interspaced Short Palindromic RepeatsColitisCollaborationsComplexControlled EnvironmentCytometryDataDefectDermatitisDiseaseEngineeringEnhancersEnvironmentFOXP3 geneFamilyFemaleFoundationsFunctional disorderGene ExpressionGene Expression ProfileGenesGeneticGenetic TranscriptionGenomicsGrantHeterozygoteHomeostasisHumanImmune ToleranceImmunologicsInflammationInternal Ribosome Entry SiteItalyLearningLesionLinkLocationLymphoidMapsMediatorMicrobeMissense MutationModelingMolecularMothersMusMutant Strains MiceMutationNuclearNuclear StructureOrganOrganismParis, FrancePathologyPatientsPhenotypePlayPredispositionProteinsRecording of previous eventsRegulationRegulatory T-LymphocyteReporterRepressionResolutionSamplingScanningSeveritiesSpecific qualifier valueStructureSymptomsT-LymphocyteTestingTissuesUnited States National Institutes of HealthVariantWorkclinically relevantcofactorconditioningforkhead proteinimmunopathologyimmunoregulationin vivoinsightmalemicrobialmultiple omicsmutantnovelpathobiontprogramspromoterresponsesingle-cell RNA sequencingsuperresolution microscopysymptomatologytranscription factortranscriptometranscriptome sequencingtranscriptomics
项目摘要
T regulatory (Treg) cells help maintain immunologic tolerance and control inflammation in many contexts. Their
dysfunction leads to multi-organ autoimmunity in FoxP3-deficient mice and human IPEX patients, with variable
clinical manifestations. Treg function and homeostasis are dependent on the transcription factor FoxP3,
encoded on ChrX, which determines a substantial portion of their specific transcriptome. Our prior work on
FoxP3 structure/function explored how FoxP3’s interactions with different cofactors within multimolecular
complexes that reside in different nuclear compartments, and condition its transactivating potential on different
transcriptional targets. Further, single-cell cytometry and transcriptomics of T cells from FOXP3-deficient
patients and mice revealed a narrow cell-intrinsic signature of the deficiency, directly controlled by FoxP3, and
a larger disease signature, conferred in a cell-extrinsic manner, that affects both Treg and conventional CD4+
T cells. We hypothesize that these components vary according to the actual FOXP3 lesion, mutations in
different interaction facets leading to different pathology, and that environmental and activation triggers
promote the unfolding of the full cell-extrinsic IPEX signature. In Aim1, to better understand the components of
Treg dysfunction in IPEX patients, we will analyze the impact of missense FOXP3 mutations by single-cell
RNAseq in CD4+ T cells from paired IPEX patients and carrier female relatives (typically mothers), in which we
distinguish Treg-like cells expressing wild-type or mutant FOXP3 through random ChrX-inactivation and SNP-
based cell identification. Effects on chromatin will also be mapped (ATACseq), and related back to
symptomatology in these patients. To enable further analysis in a genetically and environmentally controlled
environment, where sample access is not limiting, Aim2 uses CRISPR editing to introduce eight selected
missense FOXP3 mutations from IPEX patients into B6 mice, where lymphoid and tissue-resident Tregs will be
examined and profiled. Super-resolution microscopy and HiChIPseq will assess the effect of the FOXP3
mutations on localization of the mutant proteins in the nucleus, in terms of nuclear structure and enhancer-
promoter loops. We will also analyze the timing and determinants of acquisition of the dominant Treg-extrinsic
signature. Aim3 will use this FoxP3 mutant mouse panel to ask how mutation-specific transcriptional features
relate to the IPEX-relevant clinical characteristics in mice: appearance of spontaneous autoimmunity (scurfy-
like disease), susceptibility to induced autoimmunity (colitis, dermatitis). Challenges with defined microbes and
microbial molecules will test the hypothesis that clinical variability in IPEX results, at least in part, from
environmental and infectious triggers. These interconnected Aims, with complementary explorations on mice
and humans, will bring unique information on how variation in a transcription factor modulates its ability to
influence gene expression through chromatin and genomic 3D architecture, and how these relate to a
monogenic loss of tolerance in human patients.
T调节(Treg)细胞在许多情况下有助于维持免疫学耐受性和控制注射。他们的
功能障碍导致FOXP3缺陷小鼠和人IPEX患者的多器官自身免疫性
临床表现。 Treg功能和稳态取决于转录因子FOXP3,
在CHRX上编码,该CHRX确定了其特定转录组的很大一部分。我们先前的工作
FOXP3结构/功能探索了FOXP3在多分子中与不同辅因子的相互作用
驻留在不同核室中的复合物,并将其反式激活电位调节
转录目标。此外,FOXP3缺陷的T细胞的单细胞细胞术和转录组学
患者和小鼠揭示了缺乏的狭窄细胞中性特征,直接由Foxp3控制,并且
以细胞超支的方式授予的更大的疾病特征,影响Treg和常规CD4+
T细胞。我们假设这些成分根据实际的FOXP3病变而有所不同
不同的相互作用方面导致不同的病理,环境和激活触发了
促进完整的细胞超支IPEX签名的展开。在AIM1中,更好地了解
IPEX患者的Treg功能障碍,我们将通过单细胞分析错义FOXP3突变的影响
来自配对IPEX患者和载体女性亲戚(通常是母亲)的CD4+ T细胞中的RNASEQ,其中我们
通过随机的Chrx灭活和SNP-区分表达野生型或突变FOXP3的Treg样细胞
基于细胞的识别。对染色质的影响也将被映射(atacseq),并将其与
这些患者的症状学。在一般和环境控制中实现进一步的分析
环境,在不限制样品访问的情况下,AIM2使用CRISPR编辑来介绍八个选定的
来自IPEX患者的错过FOXP3突变到B6小鼠,淋巴机和组织居住的Treg将是
检查和介绍。超分辨率显微镜和Hichipseq将评估FOXP3的效果
突变蛋白在细胞核中定位的突变,就核结构和增强子而言
启动子循环。我们还将分析获得主要Treg-超支的时机和确定
签名。 AIM3将使用此FOXP3突变鼠标面板询问突变特异性转录特征
与小鼠相关的IPEX相关临床特征有关:发起自身免疫的出现(Scurfy-
像疾病一样),易感自身免疫性(结肠炎,皮炎)。定义的微生物和
微生物分子将检验以下假设:IPEX结果的临床变异至少部分来自
环境和传染性触发因素。这些相互联系的目的,以及对小鼠的完整探索
和人类,将带来有关转录因子中变异如何调节其能力的独特信息
通过染色质和基因组3D结构影响基因表达,以及它们与A的关系
人类患者的耐受性丧失。
项目成果
期刊论文数量(0)
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CHRISTOPHE O. BENOIST其他文献
CHRISTOPHE O. BENOIST的其他文献
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{{ truncateString('CHRISTOPHE O. BENOIST', 18)}}的其他基金
Specification of Treg cells: learning from FoxP3 deficiencies
Treg 细胞的规范:从 FoxP3 缺陷中学习
- 批准号:
10521755 - 财政年份:2022
- 资助金额:
$ 55.6万 - 项目类别:
T regulatory cell subsets at the microbial interface: determinism and function
微生物界面的 T 调节细胞亚群:决定论和功能
- 批准号:
9892948 - 财政年份:2017
- 资助金额:
$ 55.6万 - 项目类别:
Specification of Treg cells: FOXP3 functional facets
Treg 细胞的规格:FOXP3 功能方面
- 批准号:
9038990 - 财政年份:2015
- 资助金额:
$ 55.6万 - 项目类别:
Specification of Treg cells: FOXP3 functional facets
Treg 细胞的规格:FOXP3 功能方面
- 批准号:
8863338 - 财政年份:2015
- 资助金额:
$ 55.6万 - 项目类别:
Specification of Treg cells: FOXP3 functional facets
Treg 细胞的规格:FOXP3 功能方面
- 批准号:
9461146 - 财政年份:2015
- 资助金额:
$ 55.6万 - 项目类别:
Gut microbiome influences on autoimmune disease
肠道微生物组对自身免疫性疾病的影响
- 批准号:
8882581 - 财政年份:2014
- 资助金额:
$ 55.6万 - 项目类别:
Gene Expression and Regulatory Networks in Human Leukocytes
人类白细胞的基因表达和调控网络
- 批准号:
7854791 - 财政年份:2009
- 资助金额:
$ 55.6万 - 项目类别:
Gene Expression and Regulatory Networks in Human Leukocytes
人类白细胞的基因表达和调控网络
- 批准号:
7945283 - 财政年份:2009
- 资助金额:
$ 55.6万 - 项目类别:
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