Perforin 2 controls unconventional cytokine release from mucosal APC
穿孔素 2 控制粘膜 APC 的非常规细胞因子释放
基本信息
- 批准号:10629434
- 负责人:
- 金额:$ 45.62万
- 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:2021-08-20 至 2026-05-31
- 项目状态:未结题
- 来源:
- 关键词:AcuteAddressAdoptedAirway DiseaseAnti-Inflammatory AgentsAntigen-Presenting CellsAntigensAutomobile DrivingB-Lymphocyte SubsetsBacteriaBiochemicalBiological AssayBone MarrowCell CommunicationCell DeathCell ShapeCell membraneCell physiologyCellsCellular biologyChimera organismChronicCytolysisCytoplasmDataDendritic CellsDevelopmentDiseaseExposure toFOXP3 geneFamilyGATA3 geneGenesGenetic TranscriptionGrowth FactorHelminthsHumanIFNAR1 geneIRF4 geneITGAX geneImmunityImmunosuppressionImpairmentInfectionInflammationInflammatoryInflammatory ResponseInfluenza A virusInhalationInnate Immune ResponseInterferonsInterleukin-1InterleukinsLocationMacrophageMass Spectrum AnalysisMediatingMediatorMembraneMolecularMucous MembraneMusMyelogenousN-terminalNasal PolypsNecrosisOperative Surgical ProceduresParasitesPathway interactionsPatientsPeptide Signal SequencesPhagolysosomePopulationProtein SecretionProteinsReagentRegulatory T-LymphocyteReportingRespiratory MucosaRoleShapesSignal TransductionSpecimenT cell responseT-LymphocyteT-Lymphocyte SubsetsTestingTherapeutic InterventionTissuesVDAC1 geneVirusVirus DiseasesWorkadaptive immune responseairborne allergenchromatin immunoprecipitationchronic inflammatory diseasechronic rhinosinusitiscytokinedraining lymph nodeexperimental studyhelminth infectionimmunoregulationmass spectrometric imagingmicrobicidemouse modelmutantnovelpathogenperforin 2preventprogramsprotein aminoacid sequencepublic health relevancereceptorrespiratory infection virusrespiratory pathogenrespiratory virusresponsesingle-cell RNA sequencingtheoriestraffickingtranscription factor
项目摘要
Perforin 2 controls unconventional cytokine release from mucosal APC
Project Summary
How professional antigen presenting cell (APC) populations focally deliver cytokines to T cells for shaping the
pro-inflammatory vs. anti-inflammatory status of mucosal tissue remains incompletely understood. In particular,
cytokines that lack N-terminal peptide sequence such as the IL-1 family cytokine IL-33 can't access conventional
protein secretion pathways, which has led to the prevailing view that cell death is responsible for IL-33 release.
This project is built upon an exciting set of preliminary data demonstrating that mucosal conventional dendritic
cell (cDC) subsets, in both humans and mice, express the transmembrane pore-forming protein Perforin-2, which
at least in mice, facilitates IL-33 secretion. While in human cDC, we find Perforin-2 expression primarily in an
interferon regulatory factor 4 (IRF4) subset indicating the cDC2 lineage, in mouse cDC, we find Perforin-2 in the
CD103+ cDC1 subset known to express the transcription factors Irf8 and Batf3. Irrespective of this lineage
distinction, both human and mouse CD11c+ cells in the respiratory mucosa contain cytoplasmic IL-33 protein.
Our data demonstrate that inhibition of Perforin-2 activity prevents IL-33 release from cDC and inhibits the
proliferative expansion of a poorly understood ST2+GATA3+Foxp3+Treg subset. Given that Perforin-2 has been
shown to also regulate Type 1 IFN signaling through controlling IFNAR responsiveness, we propose an important
regulatory mechanism exists in humans and mice that is dependent upon mucosal APC that express Perforin-2.
This project tests the central hypothesis that APC require Perforin-2 as an inducible plasma membrane
conduit for unconventional cytokine delivery at the mucosal interface. Three specific aims (SA) will be
investigated. SA1 will determine whether Perforin-2+ APC predict Treg subset abundance in sinonasal mucosa
and define the transcriptional landscape of Perforin-2+ APC. SA2 will define the Perforin-2 domains required for
IL-33 release, the diversity of Perforin-2-dependent secreted molecules, and the requisite intracellular trafficking
machinery responsible for Perforin-2 plasma membrane localization during APC-T cell interactions. SA3 will
directly test whether cDC1 and/or cDC2 subsets preferentially use Perforin-2 for driving pathogen-specific T cell
responses in mouse models of respiratory virus or helminth infection. Taken together, this MIST project stands
to uncover a new paradigm for understanding how cDC instruct immunity within the respiratory mucosa.
穿孔蛋白2控制来自粘膜APC的非常规细胞因子释放
项目摘要
专业的抗原呈递细胞(APC)群体如何集中地将细胞因子递送至T细胞以塑造T细胞,
粘膜组织的促炎与抗炎状态仍然不完全清楚。特别是,
缺乏N-末端肽序列的细胞因子如IL-1家族细胞因子IL-33不能进入常规细胞因子,
蛋白质分泌途径,这导致了细胞死亡是IL-33释放的原因的流行观点。
这个项目是建立在一组令人兴奋的初步数据,表明粘膜传统树突状细胞,
人和小鼠的cDC亚群表达跨膜孔形成蛋白穿孔蛋白2,
至少在小鼠中,促进IL-33分泌。而在人cDC中,我们发现穿孔蛋白-2表达主要在
干扰素调节因子4(IRF 4)亚组指示cDC 2谱系,在小鼠cDC中,我们在小鼠cDC中发现穿孔蛋白-2(Perforin-2)。
已知表达转录因子Irf 8和Batf 3的CD 103 + cDC 1亚群。不管这个血统
区别在于,呼吸道粘膜中的人和小鼠CD 11 c+细胞都含有细胞质IL-33蛋白。
我们的数据表明,穿孔蛋白-2活性的抑制阻止了IL-33从cDC释放,并抑制了IL-33的表达。
ST 2 + GATA 3 + Foxp 3 +Treg亚群的增殖性扩增。考虑到穿孔蛋白-2已经被
显示也通过控制IFNAR反应性调节1型IFN信号传导,我们提出了一个重要的
在人类和小鼠中存在依赖于表达穿孔蛋白-2的粘膜APC的调节机制。
该项目测试了APC需要穿孔蛋白-2作为诱导质膜的中心假设
用于粘膜界面处的非常规细胞因子递送的导管。三个具体目标(SA)将是
研究了SA 1将确定穿孔蛋白-2 + APC是否预测鼻窦粘膜中的Treg亚群丰度
并定义穿孔蛋白-2 + APC的转录景观。SA 2将定义以下操作所需的穿孔蛋白-2域:
IL-33释放、穿孔蛋白-2依赖性分泌分子的多样性和必需的细胞内运输
在APC-T细胞相互作用期间负责穿孔蛋白-2质膜定位的机械。SA 3将
直接检测cDC 1和/或cDC 2亚群是否优先使用穿孔蛋白-2驱动病原体特异性T细胞
呼吸道病毒或蠕虫感染的小鼠模型的反应。总的来说,这个MIST项目
揭示了一个新的范式,以了解cDC如何指导呼吸道粘膜内的免疫。
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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De'Broski R Herbert其他文献
De'Broski R Herbert的其他文献
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{{ truncateString('De'Broski R Herbert', 18)}}的其他基金
Central role for skin sensory neurons in anti-helminth immunity
皮肤感觉神经元在抗蠕虫免疫中的核心作用
- 批准号:
10665391 - 财政年份:2023
- 资助金额:
$ 45.62万 - 项目类别:
Neuronal regulation of sinonasal Type 2 inflammation
鼻窦 2 型炎症的神经元调节
- 批准号:
10740468 - 财政年份:2023
- 资助金额:
$ 45.62万 - 项目类别:
Myeloid derived IL-33 controls Treg responses during parasite infection
骨髓源性 IL-33 控制寄生虫感染期间的 Treg 反应
- 批准号:
10463791 - 财政年份:2021
- 资助金额:
$ 45.62万 - 项目类别:
Myeloid derived IL-33 controls Treg responses during parasite infection
骨髓源性 IL-33 控制寄生虫感染期间的 Treg 反应
- 批准号:
10317582 - 财政年份:2021
- 资助金额:
$ 45.62万 - 项目类别:
Perforin 2 controls unconventional cytokine release from mucosal APC
穿孔素 2 控制粘膜 APC 的非常规细胞因子释放
- 批准号:
10283046 - 财政年份:2021
- 资助金额:
$ 45.62万 - 项目类别:
Myeloid derived IL-33 controls Treg responses during parasite infection
骨髓源性 IL-33 控制寄生虫感染期间的 Treg 反应
- 批准号:
10662289 - 财政年份:2021
- 资助金额:
$ 45.62万 - 项目类别:
Perforin 2 controls unconventional cytokine release from mucosal APC
穿孔素 2 控制粘膜 APC 的非常规细胞因子释放
- 批准号:
10472644 - 财政年份:2021
- 资助金额:
$ 45.62万 - 项目类别:
Trefoil factor proteins regulate inflammation and immunity
三叶因子蛋白调节炎症和免疫
- 批准号:
10179207 - 财政年份:2020
- 资助金额:
$ 45.62万 - 项目类别:
Physiological roles of schistosome TRP ion channels with atypical pharmacology
血吸虫 TRP 离子通道的生理作用与非典型药理学
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10078843 - 财政年份:2017
- 资助金额:
$ 45.62万 - 项目类别:
Trefoil factor proteins regulate inflammation and immunity
三叶因子蛋白调节炎症和免疫
- 批准号:
9170097 - 财政年份:2016
- 资助金额:
$ 45.62万 - 项目类别:
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