P. gingivalis-specific T cells in mice prone and resistant to periodontitis

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DESCRIPTION (provided by applicant): Periodontitis is a chronic inflammatory disease that affects 30-40% of the U.S. population. It is the leading cause of periodontal tissue destruction and tooth loss. To date, we cannot accurately predict which individuals will develop future periodontal bone destruction, leading most dental patients to undergo unnecessary treatment and exposure to undue risk. The periodontal microbiota constantly challenges the immune system, leading, in some cases, to chronic inflammation that may end in alveolar bone destruction. Inhibiting such immune responses before bone damage occurs must become the target of prevention. Our long-range goal is to define the cellular immune phenotype that predisposes an individual to destruction of the connective tissue and bone around teeth subsequent to oral infection with periodontal pathogens. Our current objective is to study the kinetics of activation and phenotype of CD4+ effector T cells specific for two Porphyromonas gingivalis gingipains (RgpA and Kgp) in a mouse strain susceptible (BALB/c) or resistant (C57BL/6) to P. gingivalis-mediated periodontal bone destruction. We hypothesize that in mice genetically susceptible to disease, RgpA- and Kgp-specific CD4+ T helper (Th) cells differentiate into bone destructive IFN-? producing Th1 cells, and into a Th17 phenotype after periodontal bone destruction has been initiated. To test this hypothesis we will use a novel antigen-specific tetramer stain to first, determine the kinetics of activation and phenotype of R/Kgp-specific effector and regulatory CD4+ T cells and the relative amount of alveolar bone destruction in P. gingivalis-colonized BALB/c and C57BL/6 mice. Concurrently, we will define the nature and timing of inflammatory cell infiltrate in the marginal gingiva. Second, we will identify the direct effect of R/Kgp- specific effector Th cells on bone levels using a series of adoptive transfer experiments. Collectively, these data will define which phenotype of R/Kgp-specific Th cells will drive the kinetics of bone destruction or protection in each mouse strain. Furthermore, these results will underpin a subsequent R01 application testing the effect of cytokines and RANKL, specifically produced by R/Kgp-specific CD4+ T cells or isotype-switched B cells, on alveolar bone homeostasis and the role of innate immunity within the marginal gingiva in mouse strains that are susceptible or resistant to periodontal bone destruction. Establishing a framework to predict future periodontal bone destruction is crucial to understanding pathogenesis of periodontal disease progression, customizing periodontal treatment, and ultimately developing a mucosal vaccine against periodontitis.