Single-cell RNA profiling identifies immune cell population shifts in diabetes associated mucosal inflammation

Poorly controlled diabetes significantly worsens periodontal disease, affecting millions worldwide, yet the mechanisms driving this destructive synergy remain unclear. We generated single-cell RNA sequencing profiles of diabetic periodontal tissue, revealing increased γ^δ T-cells, a loss of Tregs and greater neutrophil polarization as key mediators of diabetes-enhanced periodontitis. Flow cytometry confirmed significant expansion of IL-17A⁺ γ^δ+ T-cells and reduced Tregs in diabetic mice, with parallel findings of elevated CD3⁺IL-17A⁺ cells and reduced Tregs in human diabetic periodontal specimens. scRNAseq determined that diabetes caused a global increase in pro-inflammatory and a decrease in pro-resolving transcripts and enhanced inflammatory neutrophil polarization. Selective γ^δ T-cell inhibition reversed diabetes-enhanced periodontal destruction while minimally affecting normoglycemic controls and returned neutrophil infiltration to normoglycemic levels. These findings point to unique aspects of diabetes-induced dysregulation, implicate γ^δ T-cells as a driving factor and point to them as a potential therapeutic target in periodontitis and other diabetic complications.