Abstract

Oral lichen planus (OLP) is a prevalent T-cell-mediated inflammatory disease of the human oral mucosa. Intraepithelial lymphocytes (IELs) engage in close cellular interactions with epithelial keratinocytes; however, the molecular mechanisms governing their migration and dynamic crosstalk with the epithelium remain incompletely defined. Here, we demonstrate that TCRαβ + CD8αα + and TCRγδ + CD8αα + IELs represent two key CD8αα + subsets within the total IEL population in OLP lesions. Live-cell imaging revealed that CD8αα⁻ IELs exhibited slower migratory kinetics compared with their CD8αα + counterparts, confirming that surface CD8αα expression facilitates epithelial migration of CD8 + IELs. Within inflamed OLP mucosa, CD8αα + IELs produce markedly elevated levels of the pro-inflammatory cytokines IL-17 A and IFN-γ. Neutralization of these two cytokines with specific antibodies reduced the migratory capacity of both CD8αα + and CD8αα⁻ IELs, indicating that the inflammatory microenvironment promoted CD8 + IEL recruitment into lesional epithelium. GPR55 was highly expressed in CD8αα + IELs. Pharmacological blockade of GPR55 suppressed proliferation and significantly induced apoptosis in both IEL subsets. Furthermore, GPR55 antagonism robustly enhanced IEL migration and strengthened cell-to-cell contacts between IELs and oral keratinocytes (KCs). These findings identify GPR55 as a negative regulator that restricts transmigration of CD8 + IELs into the oral epithelium. Targeted GPR55 inhibition may represent a promising strategy to modulate aberrant IEL activity and preserve mucosal epithelial barrier integrity in OLP.