FimbriatedPorphyromonas gingivalisIs More Efficient than Fimbria-DeficientP. gingivalisin Entering Human Dendritic Cells In Vitro and Induces an Inflammatory Th1 Effector Response

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Abstract
Porphyromonas gingivalisis a fimbriated mucosal pathogen implicated in chronic periodontitis (CP). The fimbriae are required for invasion of the gingival mucosa and for induction of CP in animal models of periodontitis. CP is associated with infection of immature dendritic cells (DCs) byP. gingivalisin situ and with increased numbers of dermal DCs (DDCs) and mature DCs in the lamina propria. The role of fimbriae in gaining entry into human DCs and how this modulates the inflammatory and effector immune responses, however, have not been explored. To address this, we generated monocyte-derived DCs (MDDCs) in vitro which phenotypically and functionally resemble DDCs. We show here that virulent fimbriatedP. gingivalis381, in contrast to its fimbria-deficient mutant,P. gingivalisDPG3, efficiently gains entry to MDDCs in a manner dependent on active cell metabolism and cytoskeletal rearrangement. In addition, uptake of 381, unlike DPG3, induces DCs to undergo maturation, upregulate costimulatory molecules, and secrete inflammation cytokines interleukin-1β (IL-1β), IL-6, tumor necrosis factor alpha, IL-10, and IL-12. Moreover, MDDCs pulsed with 381 also stimulated a higher autologous mixed lymphocyte reaction and induced a Th1-type response, with gamma interferon (IFN-γ) being the main cytokine. Monocytes used as controls demonstrated fimbria-dependent uptake of 381 as well but produced low levels of inflammatory cytokines compared to MDDCs. When MDDCs were pulsed with recombinant fimbrillin ofP. gingivalis(10 μg/ml), maturation of MDDCs was also induced; moreover, matured MDDCs induced proliferation of autologous CD4+T cells and release of IFN-γ. Thus, these results establish the significance ofP. gingivalisfimbriae in the uptake ofP. gingivalisby MDDCs and in induction of immunostimulatory Th1 responses.