Treg cell diversity and homeostatic control
Treg 细胞多样性和稳态控制
基本信息
- 批准号:10333377
- 负责人:
- 金额:$ 51.25万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-02-11 至 2025-01-31
- 项目状态:未结题
- 来源:
- 关键词:AblationAcuteAffectAntibodiesArthritisAutoimmuneAutoimmune DiseasesAutoimmunityBackBar CodesBiological MarkersBiologyBlocking AntibodiesCD4 Positive T LymphocytesCell SeparationCell surfaceCellsCellular Indexing of Transcriptomes and Epitopes by SequencingClustered Regularly Interspaced Short Palindromic RepeatsComplexCuesCytokine ReceptorsDNADataDevelopmentDissectionEquilibriumFOXP3 geneFamilyFamily memberFeedbackFlow CytometryGenesGoalsGrantGrowth FactorHeterogeneityHomeostasisHumanIL2 geneIL7 geneImmune ToleranceImmunologic SurveillanceImmunooncologyImmunotherapyIn VitroInbred Strains MiceIndividualInflammationInflammatoryJointsKnowledgeLesionLocalesLocationLymphoid TissueMaintenanceMalignant NeoplasmsMediator of activation proteinMembrane ProteinsMiningMusPathway interactionsPatientsPeripheralPhenotypePhosphorylationPlayPopulationProcessProteomeRegulationRegulatory T-LymphocyteRestRoleSignal TransductionSorting - Cell MovementStructureSurfaceTSLP geneTestingTherapeuticThymus GlandTissuesTumor Necrosis Factor ReceptorVariantWorkantagonistbasebiomarker identificationbiomarker panelcombinatorialcytokineimmune functionimmunoregulationin vivointerestloss of functionlymphoid organmembermorphogensnoveloverexpressionreceptorsingle-cell RNA sequencingstem cellstherapeutic biomarkertherapeutic targettranscription factortranscriptometranscriptomicstumor
项目摘要
CD4+ T regulatory (Treg) that express the transcription factor FoxP3 cells play key and non-redundant
roles in maintaining immunologic tolerance and controlling inflammation. Treg proportions within CD4+ T cells
are under tight homeostatic control. There is considerable diversity to Treg cells, with differential ability to
control certain immune functions, and even tissue-resident Tregs with extra-immunologic functions. Our recent
recent single-cell RNAseq work has charted these finely, showing that Treg subsets express different effector
molecules. Treg subset structure appears very similar in mouse and humans. We hypothesize that Treg
subsets in lymphoid tissues respond to different homeostatic cues, and that these different inputs condition
specific Treg functions. (1) Our single-cell transcriptomics data, which highlighted the diversity of Treg
subphenotypes in an unbiased fashion, identified some cell surface markers for identification and sorting, but
we will expand this base by performing a combined transcriptome/proteome analysis (scRNAseq combined
with surface protein quantitation by DNA-tagged antibodies - CITE-seq) to identify a panel of flow cytometry
markers that accurately distinguish Treg subphenotypes, in both mouse and human. This will relate this novel
landscape to prior knowledge on Treg subsets, provide biomarkers, and enable cell sorting for functional
experimentation. We will assess the function of Treg subsets in regulating other immunocytes (proliferation and
differentiation), assess their developmental origin and stability (thymic or peripheral, plasticity?), and how they
vary in autoimmune or tumor lesions. (2) IL2 is the canonical controller of Treg cellsbut other common-
cytokines (IL7, 15, 21 and TSLP) and IL33 also affect Tregs. Our results show a strikingly divergent distribution
of cytokine receptors among Treg subsets, suggesting that different growth factors support them. We will use
both gain- (in vivo cytokines administration) or loss-of-function (blocking antibodies) strategies to modify Treg
subset balance, read out by flow cytometry (STAT phosphorylation, Treg subset number and activation) and
scRNAseq. (3) Most members of the large TNF Receptor (TNFR) superfamily are over-expressed in Treg cells,
and some have been shown to affect Treg maintenance and survival, but a comprehensive picture is lacking.
Our data show differential representation of TNFR across Treg subsets. We hypothesize that TNFR molecules
network with cytokine receptors to provide specific trophic signals to distinct Treg subsets. We have developed
a powerful CRISPR-based in vivo screen, based on barcoding stem cells, to evaluate how sets of genes
partake in Treg homeostasis. We will analyze the role of the entire TNFR family on maintenance of different
Treg subsets, at baseline in different lymphoid tissues and after stimulation by trophic cytokines. We will also
test several TNFRs combinatorially, to search for redundancy, complementarity or antagonism. These results
will provide a clarification and deeper understanding of the diversity of Treg populations, their control by
cytokines or surface receptors, and how they might be specifically manipulated for therapeutic intent.
表达转录因子FoxP3的CD4+ T调控(Treg)在细胞中发挥关键和非冗余作用
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)
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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:
$ 51.25万 - 项目类别:
Specification of Treg cells: learning from FoxP3 deficiencies
Treg 细胞的规范:从 FoxP3 缺陷中学习
- 批准号:
10652618 - 财政年份:2022
- 资助金额:
$ 51.25万 - 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:
$ 51.25万 - 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:
$ 51.25万 - 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:
$ 51.25万 - 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:
$ 51.25万 - 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:
$ 51.25万 - 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:
$ 51.25万 - 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:
$ 51.25万 - 项目类别:
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