Therapeutic Potential of TCRαβ ⁺ CD4 ^- CD8 ^- T Cells in Periodontitis

Periodontitis, a pervasive chronic inflammatory disorder, is distinguished by the progressive degradation of periodontal tissues and alveolar bone. Despite remarkable progress in understanding the pathogenesis of periodontitis, the involvement of TCRαβ⁺CD4^-CD8^- T cells, also known as double-negative T (DNT) cells, in the pathophysiology of this disease has not been thoroughly investigated. In this study, we observed a significant reduction in the frequency of TCRαβ⁺ DNT cells within the gingival tissues of patients afflicted with periodontitis when compared with healthy individuals. Employing a murine model, we demonstrated that the therapeutic administration of TCRαβ⁺ DNT cells resulted in a reduction of alveolar bone resorption and a decrease in inflammatory biomarkers, with the most significant effects observed at lower cell doses. Histological examination and gene expression analysis revealed a notable attenuation in the expression levels of proinflammatory cytokines. Furthermore, transcriptomic profiling elucidated the downregulation of pathways associated with neutrophil activation and interleukin-17 signaling, which are critical in the inflammatory cascade of periodontitis. Both in vitro and in vivo experiments underscored the pivotal role of perforin in TCRαβ⁺ DNT cells, which is essential for modulating periodontal inflammation and preventing alveolar bone loss. Collectively, our findings suggest that TCRαβ⁺ DNT cell therapy may represent a promising novel therapeutic strategy for periodontitis, providing valuable insights into the development of innovative treatment modalities for this prevalent oral health condition.