Lung resident niches for memory CD4 T cells

说明(申请人提供)：肺部的免疫反应对于预防呼吸道病原体至关重要，呼吸道病原体是世界上最常见的疾病原因和婴儿/儿童死亡的原因。肺中的大多数T细胞包括记忆亚群，它是在先前的抗原暴露期间产生的，与居住在淋巴组织中的原始T细胞相比，其功能得到了增强。驻留在肺组织中的记忆T细胞可以潜在地介导快速原位免疫以清除呼吸道病原体；然而，目前还没有专门促进肺部常驻免疫反应的策略。我的实验室已经确定了一种新的流感特异性记忆CD4T细胞群体，这些细胞保留并停留在肺组织中，与在脾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。这些组织驻留的记忆CD4T细胞(命名为CD4TRM)不同于循环效应记忆T细胞(TEM)，它们构成了一个新的记忆亚群，类似于组织驻留CD8T细胞亚群(CD8TRM)，发现于皮肤、肠道和其他粘膜部位。我们使用了创新的体内抗体标记和成像方法来原位研究肺CD4TRM，以及RNA下一基因测序来比较肺和脾的TRM，以确定参与肺CD4TRM生成和滞留的关键途径。我们发现了整合素CD11d在维持T细胞活化和分化中的新作用，以及通过I型干扰素在维持肺TRM维持中的作用。整合素CD11d特异性表达于小鼠和人肺中。我们的中心假设是，肺CD4TRM的产生和组织靶向涉及肺内抗原性和炎症信号以及T细胞固有的CD11d表达，而肺TRM的维持依赖于低水平的炎症。在这项拟议的研究中，我们将使用小鼠靶向缺失模型、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针对肺部居民增强保护性免疫以及了解呼吸道免疫平衡的维持提供重要的见解。

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.