Th17 cytokines differentiate obesity from obesity-associated type 2 diabetes and promote TNF production

ObjectiveT cell inflammation plays pivotal roles in obesity-associated type 2 diabetes (T2DM). The identification of dominant sources of T cell inflammation in humans remains a significant gap in understanding disease pathogenesis. It was hypothesized that cytokine profiles from circulating T cells identify T cell subsets and T cell cytokines that define T2DM-associated inflammation. MethodsMultiplex analyses were used to quantify T cell-associated cytokines in CD3/CD28-stimulated PBMCs, or B cell-depleted PBMCs, from subjects with T2DM or BMI-matched controls. Cytokine measurements were subjected to multivariate (principal component and partial least squares) analyses. Flow cytometry detected intracellular TNF in multiple immune cell subsets in the presence/absence of antibodies that neutralize T cell cytokines. ResultsT cell cytokines were generally higher in T2DM samples, but Th17 cytokines are specifically important for classifying individuals correctly as T2DM. Multivariate analyses indicated that B cells support Th17 inflammation in T2DM but not control samples, while monocytes supported Th17 inflammation regardless of T2DM status. Partial least squares regression analysis indicated that both Th17 and Th1 cytokines impact %HbA1c. ConclusionsAmong various T cell subsets, Th17 cells are major contributors to inflammation and hyperglycemia and are uniquely supported by B cells in obesity-associated T2DM.