Elucidating the Role of Regulatory T cells in Establishing and Maintaining a Th2 Niche in Skin
阐明调节性 T 细胞在皮肤中建立和维持 Th2 生态位的作用
基本信息
- 批准号:10437839
- 负责人:
- 金额:$ 69.73万
- 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:2020-07-10 至 2025-06-30
- 项目状态:未结题
- 来源:
- 关键词:AblationAdultAffectAffinityAllergic inflammationAnatomyApplications GrantsAtopic DermatitisAttenuatedBindingBiological AssayCD4 Positive T LymphocytesCellsCellular biologyChronicCoculture TechniquesCre driverCutaneousDevelopmentDiseaseDisease modelFibronectinsFunctional disorderGenesHealthHelper-Inducer T-LymphocyteHomeostasisHost DefenseHumanImmuneImmune ToleranceImmune responseImmunityInflammationInflammatoryIntegrin alpha4Interleukin 2 ReceptorLeadLifeLigandsLinkLymphocyteLymphocyte SubsetMaintenanceMicrobeMolecularMusNeonatalOrganPathogenicityPathway interactionsPatientsPeripheralPhenotypePlayPopulationPredispositionProcessProteinsRegulatory T-LymphocyteRoleSkinStaphylococcus aureusStromal CellsT cell responseT-LymphocyteTestingTh2 CellsTherapeuticTimeTissuesTranslatingantimicrobialantimicrobial peptideautoimmune inflammationcommensal microbescytokinedysbiosisexperimental studygenetic manipulationhuman diseaseimmune activationimprintin vivoin vivo evaluationinnovationinnovative technologiesinsightinterdisciplinary approachmicrobialmouse modelneonatal micenovelnovel therapeutic interventionorgan repairpathogenpediatric patientspostnatalpostnatal developmentpreventreceptorresidenceresponserestorationselective expressionsingle-cell RNA sequencingskin disorderskin organogenesistissue repairtooltumortumorigenesis
项目摘要
Project Summary/Abstract
Lymphocytes that stably reside in peripheral tissues play a critical role in defending against foreign pathogens,
suppressing tumorigenesis and facilitating organ repair. Many of these cells first establish themselves in peripheral tissues
during “critical windows” of early postnatal development and are maintained throughout life within specific
microanatomic niches, which provide the necessary factors for their survival and function. Understanding how tissue
resident lymphocytes are established and maintained is of fundamental importance in our attempts to functionally
manipulate these cells for therapeutic benefit. Abnormalities in tissue-resident lymphocytes and/or their tissue niches are
thought to contribute to autoimmune and allergic inflammation. We have discovered that regulatory T cells (Tregs) in
neonatal skin play a major role in suppressing the formation of a niche for T helper type 2 (Th2) cells in this tissue.
Transient loss of Tregs in neonatal mice results in the aberrant outgrowth of a novel subset of stromal cells that
preferentially express genes involved in type 2 immune responses (termed 'type 2 stromal cells' or `type 2 SCs').
Concurrently, a population of Th2 cells establishes residence in the same region of skin as type 2 SCs and persists into
adulthood, long after complete restoration of the Treg compartment. We hypothesize that neonatal Treg dysfunction
early in life predisposes to aberrant Th2 immune responses in adulthood by facilitating the establishment of a
pathogenic Th2 cell niche in skin. Humans with congenital loss of Tregs have dysregulated Th2 immune responses in
skin and develop severe atopic dermatitis (AD). Thus, we further postulate that Treg dysfunction early in life
contributes to the development of human AD and that augmenting Tregs in AD skin will preferentially suppress
Th2 immunity. Experiments outlined in this proposal will comprehensively define the Th2 niche in skin and determine
the consequences of this niche for lifelong susceptibility to atopic inflammation. We will first mechanistically test whether
type 2 SCs support Th2 cells and determine the molecular factors necessary for Th2 cell accumulation and maintenance in
the skin. We will then test whether the establishment of the Th2 niche in neonatal life predisposes to atopic inflammation
and aberrant AD-associated antimicrobial immune responses in adulthood. Finally, we will determine whether our
findings translate to patients with AD. We will elucidate whether Tregs are defective in skin of pediatric patients with AD,
whether a type 2 SC-Th2 cell axis exists in these patients, and whether Treg augmentation can suppress Th2 immune
responses in AD skin. We have discovered a new stromal cell population in skin and have the tools to genetically
manipulate these cells, allowing us to test a novel hypothesis centered around 'tissue imprinting' of immune cell niches
early in life. We will utilize highly innovative technology to quantify T cell responses to cutaneous microbes. In addition,
we will employ a novel ex vivo functional assay with human skin and a newly generated protein that selectively and
potently activates Tregs. Thus, the experiments outlined in this proposal represent an innovative, comprehensive, and
multidisciplinary approach to elucidate the cellular and molecular mechanisms that underpin cutaneous type 2 immune
cell niches in both mouse models and in human disease.
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)
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Michael David Rosenblum其他文献
Michael David Rosenblum的其他文献
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{{ truncateString('Michael David Rosenblum', 18)}}的其他基金
Elucidating the Role of Regulatory T cells in Establishing and Maintaining a Th2 Niche in Skin
阐明调节性 T 细胞在皮肤中建立和维持 Th2 生态位的作用
- 批准号:
10666462 - 财政年份:2020
- 资助金额:
$ 69.73万 - 项目类别:
Restoring Immune Balance in Hiddradenitis Suppurativa
恢复化脓性汗腺炎的免疫平衡
- 批准号:
10410361 - 财政年份:2020
- 资助金额:
$ 69.73万 - 项目类别:
Elucidating the Role of Regulatory T cells in Establishing and Maintaining a Th2 Niche in Skin
阐明调节性 T 细胞在皮肤中建立和维持 Th2 生态位的作用
- 批准号:
10214537 - 财政年份:2020
- 资助金额:
$ 69.73万 - 项目类别:
Restoring Immune Balance in Hiddradenitis Suppurativa
恢复化脓性汗腺炎的免疫平衡
- 批准号:
10642826 - 财政年份:2020
- 资助金额:
$ 69.73万 - 项目类别:
Elucidating the Role of Regulatory T cells in Establishing and Maintaining a Th2 Niche in Skin
阐明调节性 T 细胞在皮肤中建立和维持 Th2 生态位的作用
- 批准号:
10029624 - 财政年份:2020
- 资助金额:
$ 69.73万 - 项目类别:
Elucidating the Cellular and Molecular Mechanisms of How Regulatory T cells in Skin Regulate Fibroblast Activation and Tissue Fibrosis
阐明皮肤中调节性 T 细胞如何调节成纤维细胞活化和组织纤维化的细胞和分子机制
- 批准号:
9916710 - 财政年份:2018
- 资助金额:
$ 69.73万 - 项目类别:
Elucidating the Cellular and Molecular Mechanisms of How Regulatory T cells in Skin Regulate Fibroblast Activation and Tissue Fibrosis
阐明皮肤中调节性 T 细胞如何调节成纤维细胞活化和组织纤维化的细胞和分子机制
- 批准号:
10165504 - 财政年份:2018
- 资助金额:
$ 69.73万 - 项目类别:
Elucidating the Cellular and Molecular Mechanisms of How Regulatory T cells in Skin Regulate Fibroblast Activation and Tissue Fibrosis
阐明皮肤中调节性 T 细胞如何调节成纤维细胞活化和组织纤维化的细胞和分子机制
- 批准号:
10398162 - 财政年份:2018
- 资助金额:
$ 69.73万 - 项目类别:
Elucidating the Functional Role of Layilin Expression on Regulatory T cells in Skin
阐明 Layilin 表达对皮肤调节性 T 细胞的功能作用
- 批准号:
9372498 - 财政年份:2017
- 资助金额:
$ 69.73万 - 项目类别:
Elucidating the Fundamental Biology of Memory Regulatory T cells in Skin
阐明皮肤记忆调节 T 细胞的基本生物学
- 批准号:
8898017 - 财政年份:2014
- 资助金额:
$ 69.73万 - 项目类别:
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