A study published in *Nature* identifies a specific regulatory T cell (Treg) population, called Sm-specific Tregs, that can suppress lupus nephritis, a severe complication of systemic lupus erythematosus (SLE). The research team used biophysical affinity binding assays and high-throughput single-cell sequencing to identify a high-affinity T cell receptor (TCR) specific for the Smith (Sm) autoantigen, which is strongly associated with lupus nephritis. They then transduced this TCR into Tregs derived from SLE patients who are anti-Sm and HLA-DR15 positive. These Sm-specific Tregs were shown to suppress Sm-specific pro-inflammatory responses in vitro and significantly reduce disease progression in a humanized mouse model of lupus nephritis. Regulatory T cells are essential for maintaining immune homeostasis by suppressing autoreactive immune responses. In SLE, decreased Treg numbers or impaired Treg function contribute to disease development. Antigen-specific Tregs, such as Sm-Tregs, have shown potential as therapeutic candidates for autoimmune diseases. The study developed a platform to create antigen-specific Treg-based therapies for autoimmune diseases. In lupus nephritis, Sm-specific Tregs were identified, and their ability to suppress disease activity was evaluated in vitro and in a humanized mouse model. The study found that Sm-specific Tregs are more effective at suppressing Sm-specific auto-reactivity and restoring immune tolerance compared to polyclonal Tregs. Sm-Tregs were also shown to maintain their regulatory phenotype in vitro and in vivo, with minimal conversion to pro-inflammatory Th17 cells. In a humanized mouse model of lupus nephritis, Sm-Tregs significantly reduced disease activity, as evidenced by lower proteinuria scores and reduced kidney damage. These results suggest that Sm-Tregs could be a promising therapy for SLE. The study also highlights the importance of understanding the structural characteristics of autoantigenic peptides that bind to HLA-DR15, which can aid in the design of future TCRs for lupus nephritis and other HLA-linked autoimmune diseases. The study concludes that Sm-Tregs offer a potential therapeutic approach for SLE, with further research needed to evaluate their long-term efficacy and safety in clinical trials.A study published in *Nature* identifies a specific regulatory T cell (Treg) population, called Sm-specific Tregs, that can suppress lupus nephritis, a severe complication of systemic lupus erythematosus (SLE). The research team used biophysical affinity binding assays and high-throughput single-cell sequencing to identify a high-affinity T cell receptor (TCR) specific for the Smith (Sm) autoantigen, which is strongly associated with lupus nephritis. They then transduced this TCR into Tregs derived from SLE patients who are anti-Sm and HLA-DR15 positive. These Sm-specific Tregs were shown to suppress Sm-specific pro-inflammatory responses in vitro and significantly reduce disease progression in a humanized mouse model of lupus nephritis. Regulatory T cells are essential for maintaining immune homeostasis by suppressing autoreactive immune responses. In SLE, decreased Treg numbers or impaired Treg function contribute to disease development. Antigen-specific Tregs, such as Sm-Tregs, have shown potential as therapeutic candidates for autoimmune diseases. The study developed a platform to create antigen-specific Treg-based therapies for autoimmune diseases. In lupus nephritis, Sm-specific Tregs were identified, and their ability to suppress disease activity was evaluated in vitro and in a humanized mouse model. The study found that Sm-specific Tregs are more effective at suppressing Sm-specific auto-reactivity and restoring immune tolerance compared to polyclonal Tregs. Sm-Tregs were also shown to maintain their regulatory phenotype in vitro and in vivo, with minimal conversion to pro-inflammatory Th17 cells. In a humanized mouse model of lupus nephritis, Sm-Tregs significantly reduced disease activity, as evidenced by lower proteinuria scores and reduced kidney damage. These results suggest that Sm-Tregs could be a promising therapy for SLE. The study also highlights the importance of understanding the structural characteristics of autoantigenic peptides that bind to HLA-DR15, which can aid in the design of future TCRs for lupus nephritis and other HLA-linked autoimmune diseases. The study concludes that Sm-Tregs offer a potential therapeutic approach for SLE, with further research needed to evaluate their long-term efficacy and safety in clinical trials.