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.

项目概要 牙周病（PD）的复发是一种免疫学定义或治疗目标较差的疾病 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，CD4+T记忆细胞（TM），它可以很容易地 识别微生物抗原以做出快速而有力的反应。为此，我们将利用新的 表征了复发性 PD 的小鼠模型和牙龈 T 细胞富集的方法。在这个模型中， 时间是识别疾病发生、消退和复发的关键变量。通过建立这个 模型中，我们将能够定义“恢复”基线而不是“健康”基线状态，这更 临床准确。此外，它还允许定义多次复发事件如何逐渐影响复杂的情况 牙周相关免疫网络。初步研究表明CD4+TM在 出生后不久，由于环境抗原暴露增加，牙龈出现问题。当小鼠完全康复时 由于结扎引起的PD，在PD复发期间骨丢失率加速。最有趣的是，CD4+ TM PD 复发期间，牙龈中亚型丰富。牙龈 CD4+ 组织驻留记忆细胞 当循环 T 细胞浸润受到抑制时，可诱导骨质流失。根据这些发现，我们将测试 假设 PD 诱导的 CD4+ TM 亚型的产生和持续存在决定 PD 复发。因此，通过抑制代谢检查点来有针对性地消耗这些细胞将增强 免疫调节反应并抑制 PD 复发。三个相互关联但独立的 目的： 1) 确定牙周组织中 CD4+ TM 细胞的时空发育。在这里， 重点是了解 CD4+ TM 细胞的组成型和病理性产生，以确定 它们在牙龈免疫环境中的作用。 2) 阐明PD诱导的CD4+TM致病性。在这里，我们 将评估哪些 CD4+ TM 亚型在术后保留促炎和破骨细胞编程 PD。我们将在 CD4+ TM 亚型之间进行转录组比较，并与前人评估结果 体内功能测定以验证其致病潜力。 3）制定CD4+干预策略 TM 耗竭可防止 PD 复发。在这里，我们将采用基于代谢的策略来选择性地 消除 PD 诱导的 CD4+ TM 并增强调节性 T 细胞富集，以防止 PD 复发。这 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一名牙周病学领域富有成效的、独立的转化科学家 相关领域主要关注慢性疾病的复发。