Research ArticleMUCOSAL IMMUNITY

A dysbiotic microbiome triggers TH17 cells to mediate oral mucosal immunopathology in mice and humans

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Science Translational Medicine  17 Oct 2018:
Vol. 10, Issue 463, eaat0797
DOI: 10.1126/scitranslmed.aat0797

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Probing periodontitis pathology

Periodontitis is a common inflammatory disease that can lead to bone loss. Dutzan et al. used a mouse model of ligature-induced periodontitis and samples from patients to demonstrate that TH17 cells drive disease. People naturally deficient in TH17 cells were less likely to develop periodontitis. These pathogenic cells were dependent on the microbiome, and targeting TH17 cells with a small-molecule inhibitor dampened inflammation and bone loss in mice. Their results reveal mechanisms behind the immunopathology and could lead to effective treatments for this disease.

Abstract

Periodontitis is one of the most common human inflammatory diseases, yet the mechanisms that drive immunopathology and could be therapeutically targeted are not well defined. Here, we demonstrate an expansion of resident memory T helper 17 (TH17) cells in human periodontitis. Phenocopying humans, TH17 cells expanded in murine experimental periodontitis through local proliferation. Unlike homeostatic oral TH17 cells, which accumulate in a commensal-independent and interleukin-6 (IL-6)–dependent manner, periodontitis-associated expansion of TH17 cells was dependent on the local dysbiotic microbiome and required both IL-6 and IL-23. TH17 cells and associated neutrophil accumulation were necessary for inflammatory tissue destruction in experimental periodontitis. Genetic or pharmacological inhibition of TH17 cell differentiation conferred protection from immunopathology. Studies in a unique patient population with a genetic defect in TH17 cell differentiation established human relevance for our murine experimental studies. In the oral cavity, human TH17 cell defects were associated with diminished periodontal inflammation and bone loss, despite increased prevalence of recurrent oral fungal infections. Our study highlights distinct functions of TH17 cells in oral immunity and inflammation and paves the way to a new targeted therapeutic approach for the treatment of periodontitis.

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