Mutual interplay between IL-17-producing γδT cells and microbiota orchestrates oral mucosal homeostasis.

γδT cells are a major component of epithelial tissues and play a role in tissue homeostasis and host defense. γδT cells also reside in the gingiva, an oral tissue covered with specialized epithelium that continuously monitors the challenging dental biofilm. Whereas most research on intraepithelial γδT cells focuses on the skin and intestine epithelia, our knowledge on these cells in the gingiva is still incomplete. In this study, we demonstrate that even though the gingiva develops after birth, the majority of gingival γδT cells are fetal thymus-derived Vγ6+ cells, and to a lesser extent Vγ1+ and Vγ4+ cells. Furthermore, we show that γδT cells are motile and locate preferentially in the epithelium adjacent to the biofilm. Vγ6+ cells represent the major source of IL-17-producing cells in the gingiva. Chimeric mice and parabiosis experiments indicated that the main fraction of gingival γδT cells is radioresistant and tissue-resident, persisting locally independent of circulating γδT cells. Notably, gingival γδT cell homeostasis is regulated by the microbiota as the ratio of Vγ6+ and Vγ4+ cells was reversed in germ-free mice, and their activation state was decreased. As a consequence, conditional ablation of γδT cells results in elevated gingival inflammation and subsequent alterations of oral microbial diversity. Taken together, these findings suggest that oral mucosal homeostasis is shaped by reciprocal interplays between γδT cells and local microbiota.

Interleukin-17 is disease promoting in early stages and protective in late stages of experimental periodontitis.

Periodontitis is one of the most common infectious diseases in humans. It is characterized by a chronic inflammation of the tooth-supporting tissue that results in bone loss. However, the role and source of the pro-inflammatory cytokine interleukin-17 (IL-17) and of the cells producing it locally in the gingiva is still controversial. Th17 αß T cells, CD4+ exFoxP3+ αß T cells, or IL-17-producing γδ T cells (γδ17 cells) seem to be decisive cellular players in periodontal inflammation. To address these issues in an experimental model for periodontitis, we employed genetic mouse models deficient for either γδ T cells or IL-17 cytokines and assessed the bone loss during experimental periodontal inflammation by stereomicroscopic, histological, and µCT-analysis. Furthermore, we performed flow-cytometric analyses and qPCR-analyses of the gingival tissue. We found no γδ T cell- or IL-17-dependent change in bone loss after four weeks of periodontitis. Apart from that, our data are complementary with earlier studies, which suggested IL-17-dependent aggravation of bone loss in early periodontitis, but a rather bone-protective role for IL-17 in late stages of experimental periodontitis with respect to the osteoclastogenicity defined by the RANKL/OPG ratio.

Maturation of the neonatal oral mucosa involves unique epithelium-microbiota interactions.

Postnatal host-microbiota interplay governs mucosal homeostasis and is considered to have life-long health consequences. The intestine monolayer epithelium is critically involved in such early-life processes; nevertheless, the role of the oral multilayer epithelium remains ill defined. We demonstrate that unlike the intestine, the neonate oral cavity is immensely colonized by the microbiota that decline to adult levels during weaning. Neutrophils are present in the oral epithelium prenatally, and exposure to the microbiota postnatally further recruits them to the preamble neonatal epithelium by γδT17 cells. These neutrophils virtually disappear during weaning as the epithelium seals. The neonate and adult epithelium display distinct turnover kinetics and transcriptomic signatures, with neonate epithelium reminiscent of the signature found in germ-free mice. Microbial reduction during weaning is mediated by the upregulation of saliva production and induction of salivary antimicrobial components by the microbiota. Collectively, unique postnatal interactions between the multilayer epithelium and microbiota shape oral homeostasis.