Lung resident niches for memory CD4 T cells

记忆 CD4 T 细胞的肺驻留生态位

• 批准号: 8803453
• 负责人: Donna L. Farber
• 金额: $ 39.8万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-12-15 至 2018-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8803453
• 关键词: Ablation; Adoptive Transfer; Antibodies; Antigens; Automobile Driving; Bioinformatics; CD8B1 gene; Cells; Child Mortality; Coupled; Development; Elderly; Environment; Epithelial Cells; Generations; Homeostasis; Human; IFNAR1 gene; Image; Immune; Immune response; Immunity; In Situ; Infant; Inflammation; Inflammatory; Influenza; Integrins; Interferons; Intestines; Label; Laboratories; Lung; Lymphoid Tissue; Maintenance; Mediating; Memory; Modeling; Mus; Pathway interactions; Population; Production; RNA; Research; Respiratory System; Respiratory Tract Infections; Respiratory tract structure; Role; Signal Transduction; Skin; Spleen; Structure of parenchyma of lung; T cell differentiation; T memory cell; T-Cell Activation; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Tissues; Up-Regulation; Vaccines; Virus Diseases; adaptive immunity; cell motility; immunosuppressed; improved; in vivo; in vivo Model; influenzavirus; innovation; insight; memory CD4 T lymphocyte; mucosal site; next generation sequencing; novel; pathogen; public health relevance; respiratory; respiratory health; response; targeted imaging; terminally differentiated effector memory (TEM) T cells; trafficking

DESCRIPTION (provided by applicant): Immune responses in the lung are essential for protecting against respiratory pathogens which constitute the most prevalent cause of illness and infant/child mortality worldwide. The majority of T cells in the lung comprise the memory subset, which is generated during a previous antigen exposure, and is functionally enhanced compared to naive T cells which reside in lymphoid tissues. Memory T cells resident in lung tissue can potentially mediate rapid in situ immunity for clearing respiratory pathogens; however, there are no strategies to specifically promote lung-resident immune responses. My laboratory has identified a novel population of influenza-specific memory CD4 T cells that are retained and remain resident in lung tissue, and can promote rapid, optimal protection to influenza virus infection compared to circulating memory T cells found in spleen and lymphoid tissue. These "tissue-resident" memory CD4 T cells (designated CD4 TRM) are distinct from circulating effector-memory T cells (TEM), and constitute a new memory subset analogous to tissue-resident memory CD8 T cell subsets (CD8 TRM) identified in skin, intestines and other mucosal sites. We have used innovative in vivo antibody labeling and imaging approaches to study lung CD4 TRM in situ, as well as RNA next-gen sequencing to compare lung TRM to spleen TEM to identify key pathways involved in lung CD4 TRM generation and retention. We have uncovered a novel role for the integrin CD11d, specifically expressed in mouse and human lung CD4 TRM, in sustaining T cell activation and differentiation, and a role for inflammatory signals via type I IFN in lung TRM maintenance. Our central hypothesis is that generation and tissue targeting of lung CD4 TRM involves antigenic and inflammatory signals in the lung coupled with T cell intrinsic expression of CD11d, while maintenance of lung TRM relies on low-level inflammation. In the proposed research, we will use murine targeted deletion models, imaging, and bioinformatics to investigate the roles of inflammation, antigen stimulation, and CD11d expression in the generation and maintenance of lung TRM. Results from these studies will provide crucial insights for targeting lung resident populations to enhance protective immunity, and for understanding maintenance of immune homeostasis in the respiratory tract.

描述（由申请人提供）：肺中的免疫反应对于预防呼吸道病原体至关重要，呼吸道病原体构成了全球疾病和婴儿/儿童死亡率最普遍的原因。肺中的大多数T细胞包括在先前抗原暴露期间产生的记忆子群，并且与驻留在淋巴组织中的天真T细胞相比，在功能上得到了增强。驻留在肺组织中的记忆T细胞可能会介导清除呼吸道病原体的快速原位免疫。但是，没有策略可以特别促进肺部的免疫反应。我的实验室已经确定了保留并居住在肺组织中的新型流感特异性记忆CD4 T细胞，并且与在脾脏和淋巴组织中发现的循环记忆T细胞相比，可以促进对流感病毒感染的快速，最佳保护。这些“组织居住”的记忆CD4 T细胞（指定的CD4 TRM）与循环效应 - 内存T细胞（TEM）不同，构成了类似于组织居住的记忆存储器CD8 T细胞亚群（CD8 TRM）的新存储子集，该子集（CD8 TRM）在皮肤，肠道，肠道和其他粘膜位点中都鉴定出来。我们已经使用创新的体内抗体标记和成像方法来研究肺CD4 TRM，以及RNA下一代测序，将肺TRM与Spleen TEM进行比较，以识别与肺CD4 TRM生成和保留有关的关键途径。我们发现了整联蛋白CD11D的新作用，该作用是在小鼠和人类肺CD4 TRM中，在维持T细胞激活和分化中的作用，以及通过肺TRM维持中I型IFN的炎症信号的作用。我们的中心假设是，肺CD4 TRM的产生和组织靶向肺中涉及抗原和炎症信号，与CD11D的T细胞固有表达相连，而肺TRM的维持依赖于低水平的炎症。在拟议的研究中，我们将使用鼠类靶向缺失模型，成像和生物信息学来研究炎症，抗原刺激和CD11D表达在肺TRM的产生和维持中的作用。这些研究的结果将为靶向肺部居民增强保护性免疫和了解呼吸道中免疫稳态的维持提供至关重要的见解。