Calprotectin and CD69 affect regulatory T cell responses in periodontal disease

7.项目摘要/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。 这最终会导致成年人的牙齿脱落。它是由一种非生物微生物生物膜驱动的，这种微生物膜定居在 牙齿周围的牙龈沟。我们试图识别和描述局部对非生物的免疫反应。 导致牙周炎的生物膜。最近，CD69与调节性T细胞的结合被报道诱导 免疫抑制活性。CD69介导的调节性T细胞活化的天然配体是 钙保护素(S100A8与S100A9复合；S100A8/A9)。当在复层鳞状上皮细胞中表达时， 这种二价阳离子结合的异二聚体似乎有助于上皮内的抗菌防御。 然而，当钙保护素从中性粒细胞或感染或脱屑的角质形成细胞中释放出来时，可能会相互作用。 与CD69调节T细胞或T辅助17细胞，最终抑制免疫反应。如果是，则提供钙化保护 在牙周炎的发病过程中发挥抑制作用，这与其作为牙周炎的假定作用相反 引发炎症的“警报”。使用全局钙保护素空鼠标，我们的初步数据表明， 钙保护素抑制急性炎性浸润物的募集并限制牙周骨 实验性牙周炎模型的破坏。我们现在将探索一种新的小鼠模型 用牙龈卟啉单胞菌(PG)灌胃治疗结扎性牙周炎。我们假设 在实验性牙周炎的启动过程中通过CD69传递钙保护素信号以抑制 破坏性细胞渗入牙龈。为了检验我们的假设，我们将：1：描述差异 在实验性牙周炎初期炎症细胞的浸润性可归因于 钙保护素。2.确定CD69信号在初始阶段的招募中的作用 在钙保护素存在和不存在的情况下，炎性细胞浸润。据我们所知，我们是 第一组有数据表明钙保护素抑制先天免疫反应。我们有工具来 解释钙保护素如何通过影响牙周组织中的 使用小鼠牙周炎模型体内的CD69信号。我们将描述钙保护素和CD69是如何 Treg细胞中的信号形成了对其他效应器T细胞的免疫抑制。最终，我们将阐明 牙周组织中钙保护素是否通过CD69全球信号驱动牙周组织的保护或 牙槽骨破坏。在这里获得的结果将被用于设计治疗干预措施 旨在促进或抑制钙保护素的活性。将确定关键步骤，这些步骤可能 服从于人类的有针对性的治疗干预，旨在减少经济和个人 牙周炎的负担。

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.