The differentiation and function of CD4+ Th2 cells during allergen-induced asthma

描述(申请人提供)：哮喘是一种呼吸道炎症性疾病，其特征是由特定过敏原引起的急性、间歇性和反复发作的炎症。CD4+T细胞通过产生2型细胞因子IL-4、IL-5和IL-13，并诱导B细胞产生IgE，以响应T细胞受体(TCR)对宿主细胞上MHCII分子结合的过敏原多肽的识别。在疾病的小鼠模型和哮喘患者的模型中，静止的过敏原多肽：MHCII(PMHCII)特异性的CD4+记忆T细胞在炎症消退后可以在肺和淋巴器官中持续很长时间。在随后接触变应原时，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特异性免疫调节的靶点。然而，对于协调哮喘反应的Th2细胞的分化和维持知之甚少，这是因为追踪表达过敏原pMHCII：特异性TCRs的一小部分CD4+T细胞的挑战。为了解决这种缺乏知识的问题，我们生产了一种MHCII四聚体，其中包含一种来自屋尘螨(HDM)的Der p1蛋白的肽，屋尘螨是特应性哮喘的最常见原因。使用这个四聚体和我们设计的一种新的基于磁珠的细胞富集法，我们发现了三个过敏原特异性的CD4+T细胞亚群，它们在诱导过敏性呼吸道炎症后产生。这一应用的中心假设是，Th2效应细胞和记忆细胞在功能上不同但协同的群体是对谱系定义的转录因子之间的竞争和哮喘发病机制的反应而发展的。这项建议的目标是确定导致Th2效应细胞异质性的分子和细胞机制，并确定这些细胞如何在肺内持续存在并参与哮喘的发病机制，以便通过免疫治疗来改变它们。这种创新的方法可以提供防止记忆Th2细胞的过敏性启动或通过抗原特异性治疗消除它们的方法。

DESCRIPTION (provided by applicant): 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 differentiation and maintenance of Th2 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 three allergen- specific CD4+ T cell subsets that develop after the induction of allergic airway inflammation. The central hypothesis of this application is that functionally heterogeneous yet synergistic populations of Th2 effector and memory cells develop in response to competition between lineage-defining transcription factors and underlies asthma pathogenesis. The goals of this proposal are to identify the molecular and cellular mechanisms that lead to Th2 effector cell heterogeneity and determine how these cells persist and contribute to asthma pathogenesis in the lung so they can be modified by immunotherapy. This innovative approach could provide the means for preventing allergenic priming of memory Th2 cells or eliminating them through antigen-specific therapies.