Identification of pathogenic PD-1

Activated T cells play a pivotal pathogenic role in the progression of Sjögren's disease (SjD); however, there are currently no targeted therapies specifically designed to address them. This study aims to identify pathogenic CD8+ T cells in SjD and develop targeted therapeutic strategies. Il12b-/-Il2ra-/- mice, a murine model for overlapping primary biliary cholangitis (PBC) and SjD, were employed in this study. Pathogenic CD8+ T cells were identified through single-cell RNA sequencing (scRNA-seq) and flow cytometry analyses of samples from both SjD patients and relevant murine models. Shared T cell receptor (TCR) analysis was conducted to trace the potential precursors of pathogenic CD8+ T cells. The efficacy of PD-1-targeted CAR-T cell therapy was evaluated through the assessment of salivary gland secretory function, immunological profiles, and histopathological changes in the murine model. We identified programmed cell death protein 1 (PD-1) as a comprehensive marker of clonally expanded and activated pathogenic CD8+ T cells in the salivary glands and peripheral tissues. Flow cytometry further confirmed the activation phenotype and cytotoxicity of PD-1+CD8+ T cells in the salivary glands of patients with SjD. Notably, the number of PD-1+CD8+ T cells in the labial glands positively correlated with disease activity in SjD patients. These findings highlight the therapeutic potential of depleting PD-1+CD8+ T cells in SjD. Furthermore, PD-1-targeted CAR-T cell therapy significantly alleviated SjD symptoms in a murine model. We identified the pathogenic role of PD-1+CD8+ T cells in both SjD patients and a murine model and demonstrated the efficacy of PD-1-targeted CAR-T cell therapy in SjD model mice. Our findings suggest a promising avenue for developing clinical therapeutic strategies for SjD patients.