γδ T Cells Differentially Regulate Bone Loss in Periodontitis Models.

γδ T cells are nonclassical T lymphocytes representing the major T-cell population at epithelial barriers. In the gingiva, γδ T cells are enriched in epithelial regions adjacent to the biofilm and are considered to regulate local immunity to maintain host-biofilm homeostatic interactions. This delicate balance is often disrupted resulting in the development of periodontitis. Previous studies in mice lacking γδ T cells from birth (Tcrd-/- mice) examined the impact of these cells on ligature-induced periodontitis. Data obtained from those studies proposed either a protective effect or no impact to γδ T cells in this setting. Here, we addressed the role of γδ T cells in periodontitis using the recently developed Tcrd-GDL mice, enabling temporal ablation of γδ T cells. Specifically, the impact of γδ T cells during periodontitis was examined in 2 modalities: the ligature model and the oral infection model in which the pathogen Porphyromonas gingivalis was administrated via successive oral gavages. Ablation of γδ T cells during ligature-induced periodontitis had no impact on innate immune cell recruitment to the ligated gingiva. In addition, the number of osteoclasts and subsequent alveolar bone loss were unaffected. However, γδ T cells play a pathologic role during P. gingivalis infection, and their absence prevented alveolar bone loss. Further analysis revealed that γδ T cells were responsible for the recruitment of neutrophils and monocytes to the gingiva following the exposure to P. gingivalis. γδ T-cell ablation also downregulated osteoclastogenesis and dysregulated long-term immune responses in the gingiva. Collectively, this study demonstrates that whereas γδ T cells are dispensable to periodontitis induced by the ligature model, they play a deleterious role in the oral infection model by facilitating pathogen-induced bone-destructive immune responses. On a broader aspect, this study highlights the complex immunopathologic mechanisms involved in periodontal bone loss.

γδT Cells Are Essential for Orthodontic Tooth Movement.

Sustained mechanical forces applied to tissue are known to shape local immunity. In the oral mucosa, mechanical stress, either naturally induced by masticatory forces or externally via mechanical loading during orthodontic tooth movement (OTM), is translated, in part, by T cells to alveolar bone resorption. Nevertheless, despite being considered critical for OTM, depletion of CD4+ and CD8+ T cells is reported to have no impact on tooth movement, thus questioning the function of αßT cells in OTM-associated bone resorption. To further address the role of T cells in OTM, we first characterized the leukocytes residing in the periodontal ligament (PDL), the tissue of interest during OTM, and compared it to the neighboring gingiva. Unlike the gingiva, monocytes and neutrophils represent the major leukocytes of the PDL. These myeloid cells were also the main leukocytes in the PDL of germ-free mice, although at lower levels than SPF mice. T lymphocytes were more enriched in the gingiva than the PDL, yet in both tissues, the relative fraction of the γδT cells was higher than the αß T cells. We thus sought to examine the role of γδT cells in OTM. γδT cells residing in the PDL were mainly Vγ6+ and produced interleukin (IL)-17A but not interferon-γ. Using Tcrd-GDL mice allowing conditional ablation of γδT cells in vivo, we demonstrate that OTM was greatly diminished in the absence of γδT cells. Further analysis revealed that ablation of γδT cells decreased early IL-17A expression, monocyte and neutrophil recruitment, and the expression of the osteoclastogenic molecule receptor activator of nuclear factor-κß ligand. This, eventually, resulted in reduced numbers of osteoclasts in the pressure site during OTM. Collectively, our data suggest that γδT cells are essential in OTM for translating orthodontic mechanical forces to bone resorption, required for relocating the tooth in the alveolar bone.

Niche Specific Microbiota-Dependent and Independent Bone Loss around Dental Implants and Teeth.

Oral mucosal homeostasis is achieved by complex immunologic mechanisms, orchestrating host immunity to adapt to the physiologic functions of the various specialized niches in the oral cavity. Dental implants introduce a novel mucosal niche to the immune system to deal with. Nevertheless, the immune mechanisms engaged toward implants and whether they have broader effects are not well defined. Using a murine model, we found an accumulation of neutrophils and RANKL-expressing T and B lymphocytes in the implant-surrounding mucosa, accompanied by local bone loss. Surprisingly, the presence of implants had an impact on remote periodontal sites, as elevated inflammation and accelerated bone loss were detected in intact distant teeth. This was due to microbial dysbiosis induced by the implants, since antibiotic treatment prevented bone loss around teeth. However, antibiotic treatment failed to prevent the loss of implant-supporting bone, highlighting the distinct mechanisms mediating bone loss at each site. Further analysis revealed that implants induced chronic lymphocyte activation and increased mRNA expression of IFN-α and accumulation of IFN-α-producing plasmacytoid dendritic cells, which we previously reported as bone-destructive immune responses. Collectively, this study demonstrates that implants have a strong and broad impact on oral mucosal homeostasis, inducing periodontal bone loss in a niche-specific manner that is both microbiota dependent and independent.