Clone‐Resolved Chemical Depletion of T cells via Cellular Proximity Chemistry

Abstract T cells play a pivotal role in the development of autoimmune diseases. To mitigate autoimmune inflammation without inducing global immunosuppression, it is crucial to selectively eliminate autoreactive T cell clones while preserving the normal T cell repertoire. In this study, we applied cellular proximity chemistry to develop a T‐cell depletion method with clonal precision. Using engineered dendritic cells (DCs) with surface‐bound photosensitizers, we generated reactive oxygen species (ROS) at immune synapses, leading to the targeted death of antigen‐specific T cells in close proximity. This process induces lipid oxidation in T cell membranes, triggering ferroptosis‐like cell death. The method enables the selective elimination of specific T cell clones without affecting others, in which the clonal resolution was demonstrated by TCR sequencing. Finally, we demonstrated the efficacy of this approach in a type 1 diabetes model by selectively depleting the pathogenic 8.3 T cell clone, thereby protecting islet β cells and preserving overall T cell function. This strategy offers a promising avenue for immunosuppressive therapy that targets pathogenic T cells while maintaining overall immune integrity.