Regulatory B Cell in the Amelioration of Immune-Mediated Periodontal Disease

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Abstract. This application is for the competitive renewal of our current R01 grant titled “Regulatory B cells in the amelioration of immune-mediated periodontal disease”. Our current studies have focused on the anti- inflammatory role of B10 cells in periodontal disease tissue destruction and inflammatory bone resorption. Specifically, we demonstrated that B10 cells can be activated and expanded following triggering by specific TLR signaling and co-stimulatory molecules and thereby inhibit local inflammation and bone loss in experimental periodontitis in vivo. The observed anti-inflammatory effects are associated with IL-10 secretion by B10 cells. While substantiating the anti-inflammatory actions of these cells, the potential role of B10 cells in the resolution phase of inflammation is largely unknown. Our recent data using multiphoton intravital microscopy demonstrated co-localization of monocytes/ macrophages with transferred B10 cells in gingival tissue of LPS-induced gingivitis. Co-culture of activated B10 cells from human peripheral blood mononuclear cells (PBMC) with human monocytic cell line (THP-1)-differentiated macrophages up-regulated PD-1 expression by macrophages and production of specialized pro-resolving mediators (SPM). These effects were diminished when direct contact between B10 and macrophages was blocked. Together with the previously published findings by others, we hypothesize that i) activated B10 cells induce pro-resolving macrophage differentiation and specialized pro-resolving mediators (SPM) production via PD-L1/PD-1 ligation, and ii) that actions of SPM derived from B10- macrophage interaction enhance both B10 cell differentiation to antibody-secreting cells and pro- resolving macrophage function to promote inflammation resolution and alleviate periodontal bone loss. In this proposal, we will first determine the role of PD-L1/PD-1 ligation on B10-mediated regulation of macrophage phenotype switch and production of lipid mediators using B10-macrophage co-cultures and adoptive B10 cell transfer (Aim 1); The actions of specialized pro-resolving mediators (SPM) on B10 differentiation during B10-macrophage interaction will be determined, together with their effects on B cell- mediated pathogen clearance, and inhibition of gingival inflammation and periodontal bone loss (Aim 2); Lastly, B10-macrophage interaction on pro-resolving macrophages function, neutrophil activity, and the subsequent resolution of periodontal inflammation will be determined (Aim 3). Successful completion of this project will generate conceptual advances in our understanding of the immune regulatory cell interactions and their impact on the resolution of inflammation. If our hypothesis is correct, the studies will broaden our insights into possible role of immune checkpoint molecules PD-L1/PD-1 in inflammation resolution in periodontal disease, as well as other immune-mediated osteolytic conditions such as osteoporosis or rheumatoid arthritis.