Identification of Pathogenic PD-1⁺CD8⁺ T Cells for Effective Chimeric Antigen Receptor Therapy in a Murine Model of Sjögren Disease.

Abstract

Activated T cells play a pivotal pathogenic role in the progression of Sjögren 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 and SjD, were employed in this study. Pathogenic CD8⁺ T cells were identified through single-cell RNA sequencing and flow cytometry analyses of samples from both patients with SjD and relevant murine models. Shared T cell receptor analysis was conducted to trace the potential precursors of pathogenic CD8⁺ T cells. The efficacy of PD-1-targeted chimeric antigen receptor (CAR)-T cell therapy was evaluated through the assessment of salivary gland secretory function, immunologic profiles, and histopathological changes in the murine model. We identified 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 patients with SjD. 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 patients with SjD 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 patients with SjD.