The role of lymph node structural organization in naïve T cell decline with age

淋巴结结构组织在幼稚 T 细胞随年龄下降中的作用

• 批准号: 10730844
• 负责人: Jessica N Lancaster
• 金额: $ 59.15万
• 依托单位: MAYO CLINIC ARIZONA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10730844
• 关键词: Adoptive Transfer; Adult; Age; Aging; Architecture; Atrophic; Automobile Driving; Binding; CCL19 gene; CCL21 gene; Cell Aging; Cell Count; Cell Culture Techniques; Cell Differentiation process; Cell Maintenance; Cell Survival; Cells; Chronic; Clinical; Collagen; Communicable Diseases; Data; Development; Elderly; Environment; Fibrosis; Frequencies; Goals; Homeostasis; Human; IL7 gene; Image; Immune; Immune response; Immunity; Immunologics; Impairment; In Situ; In Vitro; Individual; Infection; Inflammation; Inflammatory; Knowledge; Ligands; Link; Lymph Node Tissue; Lymphocyte; Molecular; Mus; Outcome; Output; Pathway interactions; Phenotype; Population Decreases; Process; Proliferating; Receptor Signaling; Reticular Cell; Role; Signal Transduction; Stromal Cells; Structure; T-Lymphocyte; Testing; Three-Dimensional Imaging; Time; Tissues; Tumor Necrosis Factor Receptor; Visualization; Work; age related; aged; antifibrotic treatment; cell motility; cell type; chemokine; cytokine; density; draining lymph node; efficacy testing; emerging pathogen; flexibility; improved; in vivo; live cell microscopy; lymph node microenvironment; lymph nodes; lymphotoxin beta; lymphotoxin beta receptor; migration; novel strategies; pathogen; recruit; therapeutic development; two photon microscopy; two-photon

PROJECT SUMMARY/ABSTRACT The project goal is to understand how age-associated changes to the lymph nodes contribute to decreased survival of naïve T cells, a hallmark of immune aging. Naïve T cells are essential for resolving infections caused by newly encountered pathogens, but their number and frequency within the T cell population decrease dramatically with age. This contributes to reduced magnitude and delayed timing of the aged immune response against infectious disease. Naïve T cell survival requires constant signaling from the tissue environment, and it has been well-supported that the aged environment is defective in its ability to maintain naïve T cell homeostasis. Naïve T cells primarily interact with the tissues of the lymph nodes, organized tissue compartments strategically located throughout the body that serve as coordination centers for the immune response. Broad changes to the size and structure of the lymph nodes have been described with age, for both mice and humans; however, the mechanisms driving these changes, and how they impact naïve T cells, are unknown. Our data have revealed changes with age to the lymph node stromal cell type known as the fibroblastic reticular cell (FRC). Naïve T cells adhere to FRCs and crawl along the FRC network to navigate the lymph nodes. FRCs differentiate in situ in a process that requires continuous lymphotoxin-beta (LTβ) signaling. Mature FRCs express homeostatic cytokines that are essential for naive T cell survival and chemokines that promote interactions and motility within the lymph nodes. Homeostatic chemokines such as CCL21 have well-appreciated roles in promoting naïve T cell recruitment to and migration within the lymph nodes, but how their expression and distribution are impacted by age is not clear. In our preliminary work, we determined that lymph node stromal expression of Ltbr (lymphotoxin- beta receptor) and Ccl21 were significantly decreased with age. We also found evidence that FRC differentiation is impaired with age, in that early FRC precursors were decreased in frequency, and that there was an accumulation intermediate FRC precursors. The perturbation to FRC precursors was correlated to decreased expression of LTBR, suggesting that aged FRC precursors were unable to receive the LTβ signals necessary to complete maturation. We hypothesize that with impaired FRC differentiation, FRCs become fibrotic and spatially redistributed within the lymph node, which inhibits the interactions necessary for naïve T cell survival. In this project we will determine the role of age-associated inflammation in impairing signals through LTβR and promoting lymph node fibrosis (Aim 1), and whether increased fibrosis of the lymph node microenvironment impairs naïve T cell survival (Aim 2). Our experimental approach uses live-cell 2-photon microscopy, which enables us to visualize the interaction of naïve T cells with FRCs in real time within intact tissues. The completion of the project will support a mechanism by which the aged tissue microenvironment drives the attrition of naïve T cells. Establishing this link can lead to development of therapeutics to restore the aged lymph node stroma and promote the survival and function of naïve T cells in older individuals.

项目摘要/摘要 该项目的目标是了解与年龄相关的淋巴结变化如何有助于减少 幼稚T细胞的存活，免疫老化的标志。幼稚T细胞是解决感染所必需的 新遇到的病原体，但它们在T细胞群中的数量和频率下降 随着年龄的增长，这有助于降低老年免疫反应的幅度和延迟时间 对抗传染病幼稚T细胞的存活需要来自组织环境的持续信号， 已经得到很好的支持，即老年环境在维持幼稚T细胞稳态的能力方面存在缺陷。 幼稚T细胞主要与淋巴结组织相互作用，淋巴结组织是战略性组织区室。 位于全身，作为免疫反应的协调中心。广泛的变化， 淋巴结的大小和结构已被描述为随着年龄的增长，对于小鼠和人类;然而， 驱动这些变化的机制以及它们如何影响幼稚T细胞尚不清楚。我们的数据显示 随着年龄的变化，淋巴结基质细胞类型称为成纤维网状细胞（FRC）。初始T细胞 粘附于FRC并沿着FRC网络爬行以导航淋巴结。FRC在原位分化， 这一过程需要持续的光敏素-β（LTβ）信号传导。成熟的FRC表达稳态细胞因子 对幼稚T细胞存活和促进淋巴内相互作用和运动的趋化因子至关重要 结稳态趋化因子如CCL 21在促进幼稚T细胞增殖中具有良好的作用。 淋巴结内的募集和迁移，但它们的表达和分布如何受到 年龄不清楚。在我们的初步工作中，我们确定淋巴结间质表达Ltbr（Ltbr）， β受体）和Ccl 21随年龄增长而显著降低。我们还发现FRC分化 随着年龄的增长而受损，早期FRC前体的频率降低， 蓄积中间FRC前体。对FRC前体的扰动与减少相关 LTBR的表达，表明老年FRC前体不能接受LTβ信号， 完全成熟。我们假设，随着FRC分化受损，FRC变得纤维化， 在淋巴结内重新分布，这抑制了幼稚T细胞存活所必需的相互作用。在这 我们将确定年龄相关炎症在通过LTβR损害信号中的作用， 促进淋巴结纤维化（目的1），以及是否增加淋巴结微环境的纤维化 损害初始T细胞存活（目的2）。我们的实验方法使用活细胞双光子显微镜， 使我们能够在完整的组织中以真实的时间观察幼稚T细胞与FRC的相互作用。完成 将支持一种机制，通过这种机制，老化的组织微环境驱动了幼稚细胞的消耗。 T细胞。建立这种联系可以导致治疗的发展，以恢复老年淋巴结基质 并促进老年人中幼稚T细胞的存活和功能。