The Role of CD4+ Memory T cell Subtypes in Periodontal Disease Recurrence

CD4 记忆 T 细胞亚型在牙周病复发中的作用

• 批准号: 10642981
• 负责人: Carla Alvarez Rivas
• 金额: $ 16.21万
• 依托单位: ADA FORSYTH INSTITUTE, INC.
• 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 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10642981
• 关键词: 16S ribosomal RNA sequencing; Acceleration; Acute; Adult; Alveolar Bone Loss; Antigens; Apoptosis; Award; Bacteria; Biological Assay; Birth; CD4 Positive T Lymphocytes; CD8B1 gene; Cell Compartmentation; Cells; Cervical lymph node group; Chronic Disease; Clinical; Complex; Data; Development; Disease; Disease Progression; Disease model; Down-Regulation; Fostering; Future; Generations; Germ-Free; Gingiva; Goals; Growth; Health; Health Transition; Human; Immune; Immunologics; Immunology; Inflammation; Inflammatory; Intervention; Knowledge; Life; Ligature; Link; Literature; Memory; Metabolic; Methods; Modeling; Mucous Membrane; Mus; National Institute of Dental and Craniofacial Research; Oral; Oral Characters; Pathogenicity; Pathologic; Patients; Periodontal Diseases; Periodontitis; Phase; Phenotype; Population; Postdoctoral Fellow; Pre-Clinical Model; Process; Productivity; Property; Public Health; Recurrence; Recurrent disease; Regulatory T-Lymphocyte; Relapse; Research; Research Personnel; Resolution; Role; T cell infiltration; T memory cell; T-Lymphocyte; Testing; Therapeutic; Time; Tissue Expansion; Tissues; Tooth Loss; bone; bone loss; career; cell type; checkpoint inhibition; chronic inflammatory disease; clinically relevant; effector T cell; germ free condition; healthy aging; in vivo Model; inflammatory bone loss; lymph nodes; memory CD4 T lymphocyte; microbial; microbial colonization; microorganism antigen; mouse model; novel; oral microbiome; prevent; programs; response; spatiotemporal; therapeutic target; transcriptomics; translational scientist; translational study

Project Summary The recurrence of periodontal disease (PD) is a poorly immunologically defined or therapeutically targeted clinical challenge. Uncovering the homeostatic and pathogenic potential of long-term immune cells in periodontal tissues is crucial to revealing the cellular drivers of PD recurrence. This proposal focuses on an overlooked periodontal-associated cellular compartment, CD4+ T memory cells (TM), which can readily recognize microbial antigens for a quick and robust response. For this purpose, we will utilize a newly characterized murine model of recurrent PD and a method for gingival T-cell enrichment. In this model, time is a critical variable for recognizing disease initiation, resolution, and recurrence. By establishing this model, we will be able to define a “recovered” baseline instead of a “healthy” baseline state, which is more clinically accurate. Also, it allows defining how multiple relapse episodes incrementally impact the complex periodontally-associated immune network. The preliminary studies revealed that CD4+ TM developed in the gingiva soon after birth due to increasing environmental antigenic exposure. While the mice fully recovered from ligature-induced PD, the bone loss rate accelerated during PD recurrence. Most intriguingly, CD4+ TM subtypes are enriched in the gingiva during PD recurrence. Gingival CD4+ tissue-resident memory cells induced bone loss when circulating T cell infiltration was inhibited. Based on these findings, we will test the hypothesis that the PD-induced generation and persistence of CD4+ TM subtypes determine PD recurrence. Thus, targeted depletion of these cells by inhibiting metabolic checkpoints will enhance immune-regulatory responses and inhibit PD recurrence. There are three interconnected but independent Aims: 1) To identify the spatiotemporal development of CD4+ TM cells in periodontal tissues. Here, the focus will be on understanding the constitutive and pathologic generation of CD4+ TM cells to determine their roles in the gingival immune landscape. 2) To elucidate PD-induced CD4+ TM pathogenicity. Here, we will evaluate which CD4+ TM subtypes retain pro-inflammatory and osteoclastogenic programming after PD. We will make transcriptomic comparisons between CD4+ TM subtypes and assess the findings with ex vivo functional assays to validate their pathogenic potential. 3) To develop an intervention strategy for CD4+ TM depletion to prevent PD recurrence. Here, we will employ a metabolic-based strategy to selectively deplete PD-induced CD4+ TM and enhance regulatory T cells enrichment to prevent PD recurrence. The independence award (PAR-22-041) will foster my independent research growth and allow me to accomplish my long-term career goal to become a productive, independent translational scientist in periodontology and related fields focused on chronic diseases’ recurrence.

项目摘要 牙周病（PD）的复发是一种免疫学定义不明确或治疗靶向的疾病， 临床挑战揭示长期免疫细胞的稳态和致病潜力， 牙周组织对于揭示PD复发的细胞驱动因素至关重要。该提案的重点是 一个被忽视的牙周相关细胞区室，CD 4 + T记忆细胞（TM），它可以很容易地 识别微生物抗原，以实现快速和强大的反应。为此，我们将使用一个新的 特征性复发性PD的鼠模型和用于牙龈T细胞富集的方法。在该模型中， 时间是识别疾病开始、消退和复发的关键变量。通过建立这个 模型，我们将能够定义一个“恢复”的基线，而不是一个“健康”的基线状态，这是更 临床上准确。此外，它允许定义多个复发事件如何递增地影响复合体 周期相关免疫网络初步研究表明，CD 4 + TM在 牙龈出生后不久，由于增加环境抗原暴露。当老鼠完全恢复时 从结扎诱导的PD，骨丢失率加快PD复发。最有趣的是，CD 4 + TM 亚型在PD复发期间在牙龈中富集。牙龈CD 4+组织驻留记忆细胞 当循环T细胞浸润被抑制时，诱导骨丢失。根据这些发现，我们将测试 PD诱导的CD 4 + TM亚型的产生和持续性决定PD的假设 复发因此，通过抑制代谢检查点来靶向消耗这些细胞将增强 免疫调节反应和抑制PD复发。有三个相互联系但独立的 目的：1）研究牙周组织中CD 4 + TM细胞的时空发育规律。这里 重点将是了解CD 4 + TM细胞的组成和病理生成，以确定 它们在牙龈免疫中的作用。2)阐明PD诱导的CD 4 + TM致病性。这里我们 将评估哪些CD 4 + TM亚型在治疗后保留促炎和破骨细胞生成编程， 警局我们将在CD 4 + TM亚型之间进行转录组学比较，并评估与转录水平相关的结果。 体内功能测定以验证其致病潜力。3)制定CD 4+干预策略 TM耗竭以防止PD复发。在这里，我们将采用基于代谢的策略， 消耗PD诱导的CD 4 + TM并增强调节性T细胞富集以防止PD复发。的 独立奖（PAR-22-041）将促进我的独立研究成长，并让我完成 我的长期职业目标是成为牙周病学的一名多产，独立的翻译科学家， 相关领域关注慢性病复发。