Gingival Langerhans cells regulate plasticity of P. gingivalis-specific T cells

7. 项目摘要/摘要

7. PROJECT SUMMARY / ABSTRACT 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. Understanding its immunopathogenesis is important for developing cell-mediated vaccines and because we cannot accurately predict the development of periodontitis, leading dental patients to undergo unnecessary treatment. What is known is that activated CD4+ T helper cells (Th) contribute to alveolar bone destruction by influencing osteoclastogenesis. What remains unknown is the relative roles of mucosal antigen presenting cells on the priming and plasticity of CD4+ T cells after encountering a keystone pathogen. Our long-range goal is to identify and characterize the components of the local immune response to periodontal pathogens that predisposes an individual to periodontitis. Our current objective is to determine the kinetics of differentiation and plasticity of gingival Th17 and iTreg cells that is modulated by Langerhans cells (LCs) after oral colonization with Porphyromonas gingivalis (Pg). We have preliminary data that suggests that absence of LCs does not alter the clonal expansion of activated CD4+ T cells but prevents the differentiation of Th17 cells specific for Pg gingipain virulence factors. We hypothesize that persistent oral colonization with Pg induces mucosal antigen presenting cells (i.e. LCs) to differentially favor the late developmental re-programming of gingival Th17 cells into IFN-γ expressing Th cells and iTregs into IL-17A- or IFN-γ-expressing cells. To test our hypothesis, we will first determine the kinetics of Th17 and iTreg persistence and conversion to IFN-γ− or IL-17A-expressing cells in the gingiva of mice following oral inoculation with Pg. Second, determine the role of oral LCs in driving Th17 and iTreg plasticity following oral colonization with Pg. To the best of our knowledge, we are the first group in the world to have engineered an I- Ab tetramer displaying native epitopes from Pg, which will be used to track Pg-specific CD4+ T cells after targeted ablation of LCs. Our strategy employs genetic crossing of reporter-mouse strains that unequivocally and permanently mark the developmental fate of Th17 and iTregs. We expect to determine the role of LCs as regulators of the late developmental re-programming of Pg-specific Th17 and iTreg cells either in the gingiva or cervical lymph nodes. With a deeper understanding of the mechanisms initiating periodontal disease comes opportunities through therapeutic interventions to manipulate key steps and mitigate against or prevent periodontitis.