CELL INTELLIGENCE · 肿瘤细胞治疗研究

BACKGROUND: The highly organized structures of the immunological synapse (IS) are crucial for T cell activation. PDZ domains might be involved in the formation of the IS by serving as docking sites for protein interactions. In this study, we investigate the role of the PALS1-associated tight junction protein (PATJ), which contains 10 PDZ domains, in the formation of IS and its subsequent impact on T cell activation. METHODS: To elucidate the function of PATJ, we generated murine models with conditional T cell-specific knockout of Patj and assessed T cell activation both in vitro and in vivo within the context of infection and cancer. We employed confocal microscopy to visualize the formation of IS between T cells and antigen-presenting cells in the absence of Patj . A series of PATJ truncations containing different combinations of PDZ domains was used to identify the minimal domain required for effective T cell receptor signaling. The identified active PDZ domain was then incorporated into mesothelin (MSLN)-specific chimeric antigen receptor (CAR) to evaluate its impact on CAR-T cell cytotoxicity against solid tumors. RESULTS: We observed a rapid increase in PATJ expression during T cell activation. Conditional knockout of Patj in T cells showed impaired immunity against infection and cancer in murine models. Mechanistically, ablation of Patj impedes IS formation, and thus reduces T cell activation. We further showed that engineering the active PDZ domain of PATJ into CAR structure significantly promoted the effector function of CAR-T cells. CONCLUSIONS: Our study reveals an important role of PATJ in the formation of IS and provides an approach to improve the efficacy of CAR-T therapy.