Function and Differentiation

功能与差异化

基本信息

批准号：
10886165
负责人：
MARION PEPPER
金额：
$ 86.68万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-08 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10886165
关键词：
Ablation Acute Address Affect Airway Disease Allergens Antibodies Area Asthma B-Lymphocytes BCL6 gene Binding Blood Vessels Bone Marrow CD4 Positive T Lymphocytes Cells Characteristics Clinical Complex Data Dermatophagoides pteronyssinus Development Disease model Disparity population Dose Effector Cell Eragrostis Exposure to Extrinsic asthma Family member Generations Genetic Transcription Genomics Goals Helper-Inducer T-Lymphocyte Heterogeneity Human IgE Immune Targeting Immunotherapy Incidence Inflammation Inflammatory Influenza Interleukin-1 Interleukin-10 Interleukin-13 Interleukin-2 Interleukin-4 Interleukin-5 Knockout Mice Knowledge Learning LoxP-flanked allele Lung Lymphoid Maintenance Measurable Mediating Memory Methods Microscopy Modeling Molecular Mus Pathogenesis Pathologic Pathology Peptide/MHC Complex Peptides Persons Population Population Heterogeneity Process Production Proteins Pyroglyphidae Recurrence Reporter Research Resolution Signal Transduction Structure of parenchyma of lung System T-Cell Receptor Techniques Th1 Cells Th2 Cells Time Tissues airway inflammation allergic airway inflammation associated symptom asthmatic asthmatic patient cytokine design immunopathology immunoregulation inducible Cre innovation interest interleukin-21 lymphoid organ magnetic beads memory CD4 T lymphocyte migration mouse model novel prevent progenitor programmed cell death protein 1 programs receptor response therapy development tool transcription factor

项目摘要

Project Summary/Abstract Asthma is an inflammatory disease of the airways characterized by acute, intermittent and recurrent episodes of inflammation that can be induced by a specific allergen. CD4+ T cells contribute to this process by producing the Type 2 cytokines IL-4, IL-5, and IL-13 and inducing B cell production of IgE in response to T cell receptor (TCR) recognition of allergen peptides bound to MHCII molecules on host cells. In both murine models of disease and asthmatic patients, quiescent allergen peptide:MHCII (pMHCII)-specific CD4+ memory T cells can persist in lungs and lymphoid organs long after resolution of inflammation. Upon subsequent exposure to allergen, CD4+ memory T cells rapidly drive asthma-induced immunopathology making these cells attractive targets for allergen- specific immune modulation. Little is known, however, about the function and maintenance of Th2 memory cells that orchestrate the asthmatic response due to the challenge of tracking small populations of CD4+ T cells that express allergen pMHCII: specific TCRs. To address this lack of knowledge, we produced an MHCII tetramer containing a peptide from the Der p1 protein of the house dust mite (HDM), Dermatophagoides pteronyssinus, the most common cause of atopic asthma. Using this tetramer and a novel magnetic bead-based cell enrichment method of our design, we have found that IL-2 dependent, functionally heterogeneous populations of Th2 tissue resident memory cells reside in the lung for long periods of time. The central hypothesis of this application is that these distinct yet synergistic populations of Th2 “effector Trm” and B cell helping “Tfh Trm” contribute to asthma pathogenesis in unique ways. The goals of this proposal are to identify the molecular and cellular mechanisms that lead to Th2 Trm cell heterogeneity and determine how these cells persist in different regions of the lung. This innovative approach could provide the means for targeting specific pathologic functions of memory Th2 cells by immunotherapy or eliminating them altogether.

项目摘要/摘要哮喘是一种以急性，间歇性和复发性发作为特征的气道的炎症性疾病特定过敏原诱导的炎症。 CD4+ T细胞通过产生 2型细胞因子IL-4，IL-5和IL-13，以及响应T细胞受体（TCR）的IgE的B细胞产生识别与宿主细胞上MHCII分子结合的过敏原petides。在疾病的鼠模型和哮喘患者，静止过敏原肽：MHCII（PMHCII）特异性CD4+记忆T细胞可以持续存在炎症解决后很长时间后肺和淋巴器官。随后接触过敏原，CD4+ 记忆T细胞迅速驱动哮喘诱导的免疫病理学，使这些细胞具有吸引力的过敏原靶标特异性免疫调节。但是，关于TH2存储单元的功能和维护知之甚少由于追踪少量的CD4+ T细胞种群的挑战，该哮喘反应构成了哮喘反应表达过敏原PMHCII：特定TCR。为了解决这种缺乏知识，我们生产了一个MHCII四聚体包含来自房屋粉尘螨（HDM）的Der P1蛋白的胡椒蛋白特应性哮喘的最常见原因。使用此四聚体和一种新型的磁珠基细胞富集设计方法，我们发现IL-2依赖于TH2组织的功能异质种群居民记忆细胞长时间居住在肺部。该应用程序的中心假设是 Th2“效应器TRM”和B细胞的这些独特但协同的人群有助于“ TFH TRM”有助于哮喘发病机理以独特的方式。该建议的目标是确定分子和细胞机制这导致Th2 TRM细胞异质性，并确定这些细胞在肺的不同区域如何持续。这种创新的方法可以为瞄准记忆的特定病理功能提供手段通过免疫疗法或完全消除细胞。