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.

项目概要/摘要哮喘是一种气道炎症性疾病，其特征是急性、间歇性和反复发作。由特定过敏原诱导的炎症通过产生 CD4+ T 细胞来促进这一过程。 2 型细胞因子 IL-4、IL-5 和 IL-13 以及诱导 B 细胞响应 T 细胞受体 (TCR) 产生 IgE 在小鼠疾病模型和宿主细胞上识别与 MHCII 分子结合的过敏原肽。哮喘患者中，静态过敏原肽：MHCII (pMHCII) 特异性 CD4+ 记忆 T 细胞可以持续存在炎症消退后很长时间内，在随后暴露于过敏原时，CD4+仍会影响肺部和淋巴器官。记忆 T 细胞迅速驱动哮喘诱发的免疫病理学，使这些细胞成为过敏原的有吸引力的目标。然而，人们对 Th2 记忆细胞的功能和维持知之甚少。由于追踪少量 CD4+ T 细胞的挑战而协调哮喘反应表达过敏原 pMHCII：特异性 TCR 为了解决这一知识的缺乏，我们生产了 MHCII 四聚体。含有来自屋尘螨 (HDM)、屋尘螨 Dermatophagoides pteronyssinus 的 Der p1 蛋白的肽，使用这种四聚体和新型磁珠细胞富集是特应性哮喘的最常见原因。根据我们设计的方法，我们发现 Th2 组织的 IL-2 依赖性、功能异质群体常驻记忆细胞在肺中驻留很长一段时间。该应用的中心假设是：这些独特但协同的 Th2“效应 Trm”和 B 细胞群体有助于“Tfh Trm”导致哮喘该提案的目标是确定分子和细胞机制。导致 Th2 Trm 细胞异质性并决定这些细胞如何在肺部不同区域持续存在。这种创新方法可以提供针对记忆 Th2 特定病理功能的方法通过免疫疗法或完全消除细胞。