Abstract
Chimeric Antigen Receptor (CAR) regulatory T cells (Tregs) represent a promising cell-based therapy for autoimmune diseases, yet conventional designs require multistep activation before suppressing pathogenic cells, limiting precision and efficacy. We developed a "3-in-One" CAR Treg platform targeting Programmed cell death protein 1 (PD-1), enabling direct engagement with, activation by, and suppression of PD-1+ effector conventional T cells (eTconvs), key drivers of autoimmune inflammation. PD-1CAR Tregs stably expressed CAR and FoxP3, displayed high CD25, and upon PD-1 engagement, upregulated Ki67, IL-10, and TGF-β1 without producing IFNγ or IL-2, maintaining a committed regulatory phenotype. Functionally, they inhibited T cell proliferation and preferentially reduced PD-1+ eTconvs, a specificity not seen in conventional Tregs. Moreover, PD-1CAR Tregs promoted oligodendrocyte precursor cell differentiation and secreted CCN3, a reparative factor, suggesting dual benefits in immune regulation and neuronal repair. These findings establish PD-1CAR Tregs as a unique therapy with both targeted suppression and tissue repair potential.