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Review
. 2020 Jan 3;5(43):eaau4594.
doi: 10.1126/sciimmunol.aau4594.

Regulation of host-microbe interactions at oral mucosal barriers by type 17 immunity

Sarah L Gaffen  1 , Niki M Moutsopoulos  2
Affiliations
Review

Regulation of host-microbe interactions at oral mucosal barriers by type 17 immunity

Sarah L Gaffen et al. Sci Immunol. .

Abstract

The oral mucosa is a primary barrier site and a portal for entry of microbes, food, and airborne particles into the gastrointestinal tract. Nonetheless, mucosal immunity at this barrier remains understudied compared with other anatomical barrier sites. Here, we review basic aspects of oral mucosal histology, the oral microbiome, and common and clinically significant diseases that present at oral mucosal barriers. We particularly focus on the role of interleukin-17 (IL-17)/T helper 17 (TH17) responses in protective immunity and inflammation in the oral mucosa. IL-17/TH17 responses are highly relevant to maintaining barrier integrity and preventing pathogenic infections by the oral commensal fungus Candida albicans On the other hand, aberrant IL-17/TH17 responses are implicated in driving the pathogenesis of periodontitis and consequent bone and tooth loss. We discuss distinct IL-17-secreting T cell subsets, emphasizing their regulation and function in oropharyngeal candidiasis and periodontitis.

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Conflict of interest statement

Competing interests. SLG is recipient of US Patent #10,160,974, “Engineered cytokine- and chemokine-expressing Candida albicans strains and methods of use.” SLG has consulted for Merck, Abbvie and Eli Lilly. The authors declare no other competing interests.

Figures

Figure 1.
Figure 1.. Histology of the oral mucosa, a barrier for environmental stimuli and commensal microbiota.
The oral mucosa is a frequent site of first encounter. Airborne particles (allergens), commensal microbes and food are exposed to the mouth before transiting to the gastrointestinal tract or airway. The oral mucosa is composed of a stratified squamous epithelium with varying characteristics at different oral anatomical locations. Lining epithelium (buccal, inner lip, floor of mouth) is multilayered, non-keratinized and with rich vascularity in the submucosal areas. Immune cells are present scattered within and underlying the epithelium. In the dorsum and lateral borders of the tongue, the oral mucosa becomes specialized, with discrete formations called papillae. Within the papillae are taste buds, the chemoreceptors of taste. Within the tonsils the epithelium becomes invaginated, forming crypts. Crypt epithelium is often just a single layer with interspersed M cells, which can sample antigens and transfer them to underlying immune cells, which form germinal centers. Another area of vulnerable epithelium lies in the gingival crevice. Crevicular epithelium becomes very thin at the base of the pocket where it connects to the tooth surface. This epithelial barrier is constantly exposed to the tooth-adherent microbial biofilm. Immune cells are abundant in this region and neutrophils continuously transmigrate through from the tissue into the crevice.
Figure 2.
Figure 2.. Oral mucosal histology.
Oral microbiota are linked to the initiation and/or pathogenesis of systemic diseases such as colon cancer, infectious endocarditis, ventilator-associated pneumonia and Alzheimer’s disease. Periodontitis has been associated with systemic conditions such as cardiovascular disease, diabetes, pregnancy complications and rheumatoid arthritis.
Figure 3.
Figure 3.. Regulation/function of Th17 in periodontal immunity and inflammation.
In health, the trigger for Th17 cell accumulation in the gingiva is ongoing damage that occurs during mastication. Resulting local tissue damage triggers IL-6 production from epithelial cells, which induces Th17 cell accumulation in an antigen-dependent manner. These health-associated Th17 cells secrete IL-17 and mediate IL-17-dependent protective barrier responses, such as antimicrobial defense. In periodontitis, Th17 cells are expanded in the gingiva in response to a dysbiotic microbiome. Disease-associated microbiota trigger IL-6- and IL-23-dependent accumulation of Th17 cells. Disease-causing Th17 cells drive periodontal bone loss through excessive neutrophil recruitment and related immunopathology.
Figure 4.
Figure 4.. Regulation/function of IL-17 secreting cells during candidiasis.
C. albicans is a dimorphic commensal fungus that colonizes the human oral cavity. In health, this organism is found mainly in an avirulent yeast form, and triggers little or no immune activity in the oral mucosa. Upon conversion to a hyphal state, C. albicans exposes β-glucans in the cell wall that activate the Dectin-1/CARD9 pathway in APCs. APCs consequently secrete Th17-skewing cytokines such as IL-1, IL-6, and IL-23, driving IL-17 production from antigen-specific Th17 cells. Hyphae also secrete the peptide candidalysin, which damages oral epithelial cells and triggers secretion of DAMPs such as IL-1 and IL-36. These signals activate innate IL-17-producing cells. IL-17 binds to its receptor on oral epithelial cells and induces antimicrobial effectors, including CXC chemokines and G-CSF that promote a neutrophil response and β-defensins that have direct fungicidal activity.
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