Calprotectin and CD69 affect regulatory T cell responses in periodontal disease

7.项目概要/摘要 牙周炎是一种以牙周组织破坏为特征的慢性炎症性疾病 最终导致成年人牙齿脱落。它是由一个生态失调的微生物生物膜驱动的， 牙齿周围的牙龈沟。我们试图确定和表征局部免疫反应的生态失调 导致牙周炎的生物膜。最近，据报道，CD 69对调节性T细胞的参与诱导了 免疫抑制活性。CD 69介导的调节性T细胞活化的天然配体是 钙卫蛋白（S100 A8与S100 A9复合; S100 A8/A9）。当在复层鳞状上皮中表达时， 这种二价阳离子结合异二聚体复合物似乎有助于上皮内抗微生物防御。 然而，当从中性粒细胞或感染或脱落的角质形成细胞中释放时，钙卫蛋白可能与 与CD 69 + T调节或T辅助17细胞，最终抑制免疫应答。如果是，钙卫蛋白 可能在牙周炎的发生过程中起到抑制作用，这与其作为牙周炎的假定作用相反。 促炎“警报素”。使用一个全球钙卫蛋白null小鼠，我们的初步数据表明，净 钙卫蛋白的作用抑制急性炎症浸润的募集并限制牙周骨 在结扎诱导的实验性牙周炎模型中的破坏。我们现在将探索一种新的小鼠模型 牙龈卟啉单胞菌（Porphyromonas gingivalis，Pg）灌胃致敏的结扎诱导牙周炎。我们假设 钙卫蛋白信号通过CD 69在实验性牙周炎的启动，以抑制 破坏性的细胞渗入牙龈为了验证我们的假设，我们将：1：描述差异 在实验性牙周炎的初始阶段， 钙卫蛋白2.确定CD 69信号传导对初始细胞的募集的贡献。 在存在和不存在钙卫蛋白的情况下炎性细胞浸润。据我们所知，我们是 第一组的数据表明钙卫蛋白抑制先天免疫反应。我们有工具 解释钙卫蛋白如何通过影响牙龈中的整体免疫细胞， 使用牙周炎小鼠模型的体内CD 69信号传导。我们将描述钙卫蛋白和CD 69 Treg细胞中的信号传导形成对其它效应T细胞的免疫抑制。最终，我们将阐明 钙卫蛋白是否通过牙龈中的CD 69全局信号传导驱动牙周组织的保护， 牙槽骨破坏。这里获得的结果将用于设计治疗干预措施 旨在增强或抑制钙卫蛋白的活性。将确定关键步骤， 适用于人类的靶向治疗干预，旨在减少经济和个人 牙周炎负担。

7. PROJECT SUMMARY / ABSTRACT Periodontitis is a prevalent chronic inflammatory condition characterized by the destruction of the periodontium that ultimately leads to tooth loss in adults. It is driven by a dysbiotic microbial biofilm that colonizes the gingival sulcus around teeth. We seek to identify and characterize the local immune response to the dysbiotic biofilm that leads to periodontitis. Recently, CD69 engagement on regulatory T cells was reported to induce immunosuppressive activities. A natural ligand for CD69-mediated activation of regulatory T cells is calprotectin (S100A8 complexed to S100A9; S100A8/A9). When expressed in stratified squamous epithelia, this divalent cation-binding heterodimeric complex appears to contribute to intraepithelial antimicrobial defense. When released from neutrophils or infected or desquamating keratinocytes, however, calprotectin may interact with CD69+ T regulatory or T helper 17 cells, ultimately suppressing the immune response. If so, calprotectin may suppressive functions during the initiation of periodontitis contrary to its postulated role as a proinflammatory “alarmin”. Using a global calprotectin null mouse, our preliminary data suggest that the net effect of calprotectin dampens the recruitment of an acute inflammatory infiltrate and limits periodontal bone destruction in a ligature-induced experimental periodontitis model. We will now explore a novel murine model of ligature-induced periodontitis primed with Porphyromonas gingivalis (Pg) gavage. We hypothesize that calprotectin signals through CD69 during the initiation of experimental periodontal inflammation to dampen a destructive cellular infiltrate into the gingiva. To test our hypothesis, we will: 1: Characterize the differences in the inflammatory cell infiltrate during the initial stage of experimental periodontitis attributable to calprotectin. 2. Determine the contribution of CD69 signaling to the recruitment of the initial inflammatory cell infiltrate in the presence and absence of calprotectin. To our knowledge, we are the first group with data suggesting that calprotectin dampens the innate immune response. We have the tools to explain how calprotectin contributes to recruitment of innate immune cells in the gingiva by affecting global CD69 signaling in vivo using a murine model of periodontitis. We will characterize how calprotectin and CD69 signaling in Treg cells shapes immunosuppression on other effector T cells. Ultimately, we will elucidate whether calprotectin via CD69 global signaling in the gingiva drives either protection of periodontal tissues or destruction of alveolar bone. The results obtained here will be used to design therapeutic interventions directed at boosting or inhibiting the activity of calprotectin. Critical steps will be identified that might be amenable to targeted therapeutic intervention in humans aiming at reducing the economic and personal burden of periodontitis.