权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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：
10472644
负责人：
De'Broski R Herbert
金额：
$ 45.5万
依托单位：
UNIVERSITY OF PENNSYLVANIA
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：
https://reporter.nih.gov/project-details/10472644
关键词：
Acute Address Adopted Airway Disease Anti-Inflammatory Agents Antigen-Presenting Cells Antigens Automobile Driving B-Lymphocyte Subsets Bacteria Biochemical Biological Assay Bone Marrow Cell Communication Cell Death Cell Shape Cell membrane Cell physiology Cells Cellular biology Chimera organism Chronic Data Dendritic Cells Development Disease Exposure to FOXP3 gene Family GATA3 gene Genes Genetic Transcription Growth Factor Helminths Human IFNAR1 gene IRF4 gene ITGAX gene Immunity Immunosuppression Impairment Infection Inflammation Inflammatory Inflammatory Response Influenza A virus Inhalation Interferons Interleukin-1 Interleukins Lead Location Mass Spectrum Analysis Mediating Mediator of activation protein Molecular Mucous Membrane Mus Myelogenous N-terminal Nasal Polyps Necrosis Operative Surgical Procedures Parasites Pathway interactions Patients Peptide Signal Sequences Phagolysosome Population Protein Secretion Proteins Reagent Regulatory T-Lymphocyte Reporting Respiratory Mucosa Role Shapes Signal Transduction Specimen T cell response T-Lymphocyte T-Lymphocyte Subsets Testing Therapeutic Intervention Tissues VDAC1 gene Virus Virus Diseases Work adaptive immune response airborne allergen chromatin immunoprecipitation chronic inflammatory disease chronic rhinosinusitis cytokine draining lymph node experimental study helminth infection immunoregulation macrophage mass spectrometric imaging microbicide mouse model mutant novel pathogen perforin 2 prevent programs protein aminoacid sequence public health relevance receptor respiratory infection virus respiratory pathogen respiratory virus response theories trafficking transcription factor transcriptome sequencing

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，人类和小鼠的细胞（cDC）亚群表达跨膜成孔蛋白穿孔蛋白-2，它至少在小鼠中，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活性的抑制可以阻止IL-33从cDC中释放并抑制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。