Periodontitis (PD) is a common source of uncontrolled inflammation in obesity-associated type 2 diabetes (T2D). PD apparently fuels the inflammation of T2D and associates with poor glycemic control and increased T2D morbidity. New therapeutics are critically needed to counter the sources of periodontal infection and inflammation that are accelerated in people with T2D. The precise mechanisms underlying the relationship between PD and T2D remain poorly understood. Every major immune cell subset has been implicated in the unresolved inflammation of PD, regardless of host metabolic health. However, analyses of inflammatory cells in PD with human periodontal tissue have generally focused on mRNA quantification and immunohistochemical analyses, both of which provide limited information on immune cell function. We used a combination of flow cytometry for cell surface markers and enzyme-linked immunospot methods to assess the subset distribution and function of immune cells isolated from gingiva of people who had PD and were systemically healthy, had PD and T2D (PD/T2D), or, for flow cytometry, were systemically and orally healthy. T-cell subsets dominated the cellular immune compartment in gingiva from all groups, and B cells were relatively rare. Although immune cell frequencies were similar among groups, a higher proportion of CD11b+ or CD4+ cells secreted IFNγ/IL-10 or IL-8, respectively, in cells from PD/T2D samples as compared with PD-alone samples. Our data indicate that fundamental differences in gingival immune cell function between PD and T2D-potentiated PD may account for the increased risk and severity of PD in subjects with T2D. Such differences may suggest unexpected therapeutic targets for alleviating periodontal inflammation in people with T2D.
No abstract
T cell inflammation plays pivotal roles in obesity-associated type 2 diabetes (T2D). Multiple T cell subsets, including Th1, Th2, Th17 and regulatory T cells are critical for the development of insulin resistance in animal models of T2D. However, the relative importance of T cell subsets in human disease pathogenesis remains a critical gap in knowledge with important implications for defining the most potent inflammatory mediators of T2D. To identify T cell subsets that disproportionately contribute to T2D-associated inflammation, we broadly quantified T cell cytokine production by circulating or adipose-associated immune cells from obese subjects clinically defined as non-T2D, pre-T2D or T2D. Cytokines traditionally associated with specific T cell subsets, including IL-2 (Th1), IL-4/10/13 (Th2) and IL-17A/F (Th17), were produced at highest amounts by T2D samples. We combined cytokine outcomes with multivariate mathematical approaches to show that T cell cytokine profiles predicted T2D status with >85% accuracy. Furthermore, Th17 signature cytokines were more powerful than either Th1 or Th2 cytokines for differentiation of non-T2D from T2D samples. We conclude that Th17 cells are an underappreciated source of T cell cytokines that support inflammation and predict human T2D. Study outcomes unify contradictory claims of the importance of single cytokines and justify including Th17 cells as druggable sources of inflammation in human T2D.
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