Calprotectin and CD69 affect regulatory T cell responses in periodontal disease

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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.