Function and Differentiation

项目摘要/摘要 哮喘是一种呼吸道炎症性疾病，以急性、间歇性和反复发作为特征。 由特定过敏原引起的炎症。在这个过程中，CD4+T细胞通过产生 2型细胞因子IL-4、IL-5和IL-13诱导T细胞受体(TCR)诱导B细胞产生IgE 与宿主细胞上的MHCII分子结合的变应原多肽的识别。在两种疾病的小鼠模型和 哮喘患者静止期变应原多肽：MHCII(PMHCII)特异性CD4+记忆性T细胞可持续存在 肺部和淋巴器官在炎症消退后很久才出现。在随后的过敏原暴露后，CD4+ 记忆T细胞迅速驱动哮喘诱导的免疫病理，使这些细胞成为过敏原的靶标。 特殊的免疫调节。然而，关于Th2存储单元的功能和维护知之甚少 它协调了哮喘反应，因为追踪少量的CD4+T细胞是一项挑战 快速变应原pMHCII：特异性TCRs。为了解决这种缺乏知识的问题，我们制造了一个MHCII四聚体 含有屋尘螨(HDM)的Der p1蛋白的多肽， 特应性哮喘最常见的原因。使用该四聚体和一种新型的磁珠电池富集剂 我们的设计方法，我们发现依赖IL-2的，功能不同的Th2组织群体 常驻记忆细胞在肺中驻留很长时间。这个应用程序的中心假设是 Th2“效应器Trm”和帮助“Tfh Trm”的B细胞的这些不同而又协同的群体有助于哮喘的发生。 以独特的方式发病。这项提议的目标是确定分子和细胞机制。 这导致了Th2Trm细胞的异质性，并决定了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Th2的特定病理功能的手段 通过免疫疗法或完全消除细胞。

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.