Function and Differentiation

项目概要/摘要 哮喘是一种呼吸道炎症性疾病，其特征是急性、间歇性和反复发作， 由特定过敏原引起的炎症。CD 4 + T细胞通过产生CD 4 + 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 识别与宿主细胞上的MHCII分子结合的过敏原肽。在两种鼠疾病模型中， 在哮喘患者中，静止变应原肽：MHCII（pMHCII）特异性CD 4+记忆T细胞可持续存在， 肺部和淋巴器官的炎症消退后很长时间。在随后暴露于过敏原时，CD 4 + 记忆T细胞快速驱动哮喘诱导的免疫病理学，使这些细胞成为过敏原的有吸引力的靶点， 特异性免疫调节然而，对Th 2记忆细胞的功能和维持知之甚少 由于追踪小群体的CD 4 + T细胞的挑战， 表达过敏原pMHCII：特异性TCR。为了解决这种知识的缺乏，我们生产了MHCII四聚体， 含有来自屋尘螨（HDM）Dermatophagoides pteronyssinus的Der p1蛋白的肽， 过敏性哮喘最常见的病因使用这种四聚体和一种新的基于磁珠的细胞富集 我们的设计方法，我们发现IL-2依赖性，功能异质性的Th 2组织群体， 驻留记忆细胞长时间驻留在肺中。本申请的中心假设是， Th 2“效应Trm”和B细胞帮助“Tfh Trm”的这些不同但协同的群体促成哮喘 独特的发病机制。本提案的目标是确定分子和细胞机制 导致Th 2 Trm细胞异质性并决定这些细胞如何在肺的不同区域持续存在。 这种创新的方法可以提供针对记忆Th 2的特定病理功能的手段。 通过免疫疗法或完全消除它们。

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.