Lymph node stromal cells coordinate immune cell environments during Aspergillus fumigatus infection

烟曲霉感染期间淋巴结基质细胞协调免疫细胞环境

基本信息

  • 批准号:
    10751936
  • 负责人:
  • 金额:
    $ 5.26万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2023
  • 资助国家:
    美国
  • 起止时间:
    2023-07-01 至 2027-06-30
  • 项目状态:
    未结题

项目摘要

Project Summary The opportunistic fungal pathogen Aspergillus fumigatus presents a major health concern in immunodeficient and critically ill patients, with invasive disease contributing to high mortality rates. Infection with A. fumigatus elicits a diverse adaptive CD4 T cell response. Our preliminary data have demonstrated distinct TH1 and TH17 spatial neighborhoods within mediastinal lymph nodes (LNs) during A. fumigatus airway infection. This spatial organization positions activated CD4 T cells to receive tailored signals (e.g., antigens, cytokines) for optimal effector cell differentiation and function. Lymph node stromal cells (LNSCs) are known to provide guidance cues for immune cell trafficking during monotypic effector T cell responses. However, the mechanisms by which distinct TH1 and TH17 microenvironments are concurrently established within LNs remain unknown. Defining these mechanisms will offer insights into the functional importance of LN microenvironments in establishing human immunity to infection and inflammatory disorders for the identification of novel therapeutic strategies. Based upon our single-cell RNA-sequencing and flow cytometric analyses of FRC and effector T cell subsets during A. fumigatus challenge, we propose that (i) FRC subsets establish spatially distinct TH1 and TH17 neighborhoods by dynamically regulating chemotactic receptor-ligand axes, such as CXCR3:CXCL9/CXCL10 and CCR6:CCL20 and that ii) these neighborhoods can persist after pathogen clearance. We will address these hypotheses in a clinically relevant murine model of invasive pulmonary aspergillosis. In Specific Aim 1, we will characterize distinct spatiotemporal microenvironments formed by CD4 T cells and FRCs in A. fumigatus infection by applying spatial transcriptomic profiling followed by high-content immunofluorescence methods paired with a novel computational approach for image analysis. In Specific Aim 2, we will define the functional role of CD4 T cell spatial organization in A. fumigatus infection by perturbing FRC- dependent chemokine gradients in a cell type-dependent manner using FRC-specific gene targeting. We will also conduct adoptive co-transfers of A. fumigatus-specific CD4 T cells sufficient and deficient in CXCR3 and CCR6. In Specific Aim 3, we will investigate the durability of infection-driven spatial FRC diversity by studying epigenetic modifications in A. fumigatus-experienced FRCs. We will also employ high-content confocal imaging to determine whether prior infections affect FRC formation of T cell neighborhoods in subsequent infections. This study employs and develops novel genetic tools, microscopy methods, and computational approaches to generate a systems level understanding of secondary lymphoid organ immunobiology. Furthermore, this proposal is tailored for a physician-scientist in training as it investigates the mechanisms by which stromal cells induce adaptive immunity to the clinically relevant pathogen A. fumigatus, with implications for anti-fungal therapeutic strategies and vaccine development.
项目摘要 机会性真菌病原体曲霉富马图斯在免疫缺陷方面提出了主要的健康问题 患者患有侵入性疾病,导致高死亡率。烟曲霉感染 引起多种自适应CD4 T细胞反应。我们的初步数据显示了独特的TH1和TH17 富马图斯气道感染期间纵隔淋巴结(LNS)中的空间邻域。这个空间 组织位置激活CD4 T细胞以接收量身定制的信号(例如抗原,细胞因子)以获得最佳 效应细胞的分化和功能。已知淋巴结基质细胞(LNSC)提供指导线索 用于单型效应T细胞反应过程中的免疫细胞运输。但是, 在LN中同时建立了不同的TH1和TH17微环境。定义 这些机制将提供有关LN微环境在建立的功能重要性的见解 人类对鉴定新治疗策略的感染和炎症性疾病的免疫力。 基于我们的单细胞RNA测序和FRC和效应T细胞子集的流式细胞仪分析 在烟曲霉挑战赛期间,我们建议(i)FRC子集建立在空间上不同的Th1和Th17 通过动态调节趋化受体轴的邻域,例如 CXCR3:CXCL9/CXCL10和CCR6:CCL20和II)这些社区可以在病原体后持续存在 清除。我们将在侵入性肺的临床相关鼠模型中解决这些假设 曲霉病。在特定的目标1中,我们将表征由CD4形成的独特时空微环境 通过施加空间转录组分析,然后进行高含量 免疫荧光方法与新型计算方法配对,用于图像分析。在特定目标中 2,我们将通过扰动frc-来定义CD4 T细胞空间组织在烟曲霉感染中的功能作用 使用FRC特异性基因靶向以细胞类型依赖性方式,依赖性趋化因子梯度。我们将 还进行烟曲霉的CD4 T细胞的收养共同转移,足以且缺乏CXCR3和 CCR6。在特定的目标3中,我们将通过研究以感染驱动的空间FRC多样性的耐用性 烟曲霉经验丰富的FRC中的表观遗传修饰。我们还将采用高含量共焦成像 确定先前的感染是否会影响随后感染中T细胞邻居的FRC形成。这 研究采用并开发了新颖的遗传工具,显微镜方法和计算方法 产生对继发性淋巴器官免疫生物学的系统水平理解。此外,这个 提案是针对培训的医师科学家量身定制的,因为它研究了基质细胞的机制 诱导对临床相关病原体的适应性免疫,对抗真菌的影响 治疗策略和疫苗开发。

项目成果

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