Lung resident niches for memory CD4 T cells

描述（由申请人提供）：肺部的免疫反应对于防止呼吸道病原体至关重要，呼吸道病原体是全球最普遍的疾病和婴儿/儿童死亡原因。肺中的大多数T细胞包括记忆亚群，这是在以前的抗原暴露中产生的，与存在于淋巴组织中的初始T细胞相比，其功能增强。驻留在肺组织中的记忆T细胞可能介导清除呼吸道病原体的快速原位免疫；然而，目前还没有专门促进肺驻留免疫反应的策略。我的实验室已经确定了一种新的流感特异性记忆CD4 T细胞群，它们保留并留在肺组织中，与脾脏和淋巴组织中发现的循环记忆T细胞相比，它们可以促进对流感病毒感染的快速、最佳保护。这些“组织常驻”记忆CD4 T细胞（指定的CD4 TRM）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，类似于在皮肤、肠道和其他粘膜部位发现的组织常驻记忆CD8 T细胞亚群（CD8 TRM）。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CD4 TRM，以及RNA下一代测序来比较肺TRM和脾TEM，以确定肺CD4 TRM产生和保留的关键途径。我们发现了整合素CD11d在维持T细胞激活和分化中的新作用，它在小鼠和人肺CD4 TRM中特异性表达，以及通过I型IFN的炎症信号在肺TRM维持中的作用。我们的中心假设是，肺CD4 TRM的产生和组织靶向涉及肺中的抗原和炎症信号以及T细胞内在CD11d的表达，而肺TRM的维持依赖于低水平炎症。在本研究中，我们将使用小鼠靶向缺失模型、影像学和生物信息学来研究炎症、抗原刺激和CD11d表达在肺TRM产生和维持中的作用。这些研究的结果将为针对肺常住人群增强保护性免疫和理解呼吸道免疫稳态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.