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

过敏原诱发哮喘过程中CD4 Th2细胞的分化和功能

• 批准号: 8910831
• 负责人: MARION PEPPER
• 金额: $ 5.78万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-02-01 至 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8910831
• 关键词: Acute; Address; Affect; Allergens; Allergic inflammation; Anaphylaxis; Antigens; Asthma; B-Lymphocytes; BCL6 gene; Binding; CD4 Positive T Lymphocytes; Cell physiology; Cells; Cues; Cytokine Signaling; Dermatophagoides pteronyssinus; Development; Disease; Disease model; Effector Cell; Exposure to; Extrinsic asthma; Goals; Health; Helper-Inducer T-Lymphocyte; Heterogeneity; IgE; Immunotherapy; Incidence; Inflammation; Inflammatory; Interleukin-10; Interleukin-13; Interleukin-4; Interleukin-5; Kinetics; Knowledge; Lead; Ligands; Lung; Lymphoid; Maintenance; Memory; Methods; Modeling; Molecular; Mus; Organ; Pathogenesis; Pathology; Peptides; Population; Population Heterogeneity; Process; Production; Proteins; Pyroglyphidae; Recurrence; Regulatory T-Lymphocyte; Relative (related person); Research; Resolution; Role; STAT6 Transcription Factor; Symptoms; T memory cell; T-Cell Receptor; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Th2 Cells; Therapeutic; Therapeutic Effect; Work; airway inflammation; allergic airway inflammation; asthmatic patient; base; cytokine; design; high risk; immunopathology; immunoregulation; innovation; magnetic beads; memory CD4 T lymphocyte; novel; prevent; receptor; response; therapeutic development; therapy development; tool; transcription factor

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.

描述（由申请人提供）：哮喘是一种气道炎性疾病，其特征为可由特定过敏原诱导的急性、间歇性和复发性炎症发作。CD 4 + 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以响应于T细胞受体（TCR）识别与宿主细胞上的MHCII分子结合的变应原肽而促进该过程。在疾病和哮喘患者的小鼠模型中，静止的变应原肽：MHCII（pMHCII）特异性CD 4+记忆T细胞可以在炎症消退后很长时间内持续存在于肺和淋巴器官中。在随后暴露于过敏原后，CD 4+记忆T细胞迅速驱动哮喘诱导的免疫病理学，使这些细胞成为过敏原特异性免疫调节的有吸引力的靶点。然而，由于追踪表达过敏原pMHCII：特异性TCR的CD 4 + T细胞的小群体的挑战，对协调哮喘反应的Th 2细胞的分化和维持知之甚少。为了解决这种知识的缺乏，我们生产了一种MHCII四聚体，其中含有来自屋尘螨（HDM）Dermatophagoides pteronyssinus的Der p1蛋白的肽，屋尘螨是特应性哮喘的最常见原因。使用这种四聚体和我们设计的基于磁珠的新型细胞富集方法，我们发现了在诱导过敏性气道炎症后发展的三种过敏原特异性CD 4 + T细胞亚群。本申请的中心假设是Th 2效应细胞和记忆细胞的功能异质但协同的群体响应于谱系限定转录因子之间的竞争而发展，并且是哮喘发病机制的基础。该提案的目标是确定导致Th 2效应细胞异质性的分子和细胞机制，并确定这些细胞如何持续存在并有助于肺中的哮喘发病机制，以便通过免疫治疗对其进行修饰。这种创新的方法可以提供防止记忆性Th 2细胞的过敏原引发或通过抗原特异性疗法消除它们的手段。