The study investigates the potential of Smith (Sm)-specific regulatory T cells (Sm-Tregs) to suppress lupus nephritis, an autoimmune disease associated with auto-reactivity to the Sm autoantigen and the HLA-DR15 haplotype. The researchers identified a high-affinity Sm-specific T cell receptor (TCR) using biophysical binding assays and single-cell sequencing. They then transduced these TCRs into Tregs derived from patients with systemic lupus erythematosus (SLE) who are anti-Sm and HLA-DR15 positive. Compared to polyclonal mock-transduced Tregs, Sm-Tregs potently suppressed Sm-specific pro-inflammatory responses in vitro and disease progression in a humanized mouse model of lupus nephritis. These findings suggest that Sm-Tregs are a promising therapy for SLE. The study also highlights the importance of understanding the structural characteristics of autoantigen-antigenic peptide interactions for designing effective TCRs and the potential of using Sm-Tregs in clinical trials for lupus nephritis.The study investigates the potential of Smith (Sm)-specific regulatory T cells (Sm-Tregs) to suppress lupus nephritis, an autoimmune disease associated with auto-reactivity to the Sm autoantigen and the HLA-DR15 haplotype. The researchers identified a high-affinity Sm-specific T cell receptor (TCR) using biophysical binding assays and single-cell sequencing. They then transduced these TCRs into Tregs derived from patients with systemic lupus erythematosus (SLE) who are anti-Sm and HLA-DR15 positive. Compared to polyclonal mock-transduced Tregs, Sm-Tregs potently suppressed Sm-specific pro-inflammatory responses in vitro and disease progression in a humanized mouse model of lupus nephritis. These findings suggest that Sm-Tregs are a promising therapy for SLE. The study also highlights the importance of understanding the structural characteristics of autoantigen-antigenic peptide interactions for designing effective TCRs and the potential of using Sm-Tregs in clinical trials for lupus nephritis.