Aberrant Accumulation of Cell-Free DNA Activates the cGAS-STING-TBK1 Pathway of γδ T Cells to Promote the Inflammatory Responses in Oral Lichen Planus.

Oral lichen planus (OLP) is a chronic T-cell-mediated immune inflammatory disease with unclear etiology. γδ T cells are crucial for regulating T-cell activity and immune inflammatory responses. The cGAS-STING-TBK1 pathway serves as an immune sentinel for cytosolic DNA that triggers proinflammatory cytokines production and T-cell recruitment. We recently verified the co-localization of STING with γδ T cells in OLP lesions. However, the molecular mechanisms governing the roles of γδ T cells in OLP remain unknown. In the present study, we firstly investigated γδ T cells subsets and functions and found that γδ T cells were enriched in OLP lesions but reduced in peripheral blood of OLP, with the Vδ1 subset predominating. Besides, proinflammatory cytokines IL-6, IL-17, and IFN-γ secreted by OLP γδ T cells were upregulated. cfDNA levels were elevated in OLP plasma, and transfection of cfDNA into primary γδ T cells activated the cGAS-STING-TBK1 pathway, enhancing cytokine secretion, which could be reversed by the STING inhibitor H-151. Furthermore, cfDNA-OLP reduced the apoptosis rate of γδ T cells and altered their differentiation into Th17 and Foxp3