Identification of pathogenic PD‐1+CD8+ T cells for effective chimeric antigen receptor therapy in a murine model of Sjögren's disease

Objective 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. Methods 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. Results 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. Conclusion 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.