Regulatory T cells (Tregs) play an important role in maintaining immune system homeostasis. In particular, antigen-specific Tregs have been shown to be able to specifically and potently
suppress antigen autoreactivity, suggesting there is potential for the development of antigen-specific Tregs to treat autoimmune diseases. One such autoimmune disease is systemic lupus
erythematosus (SLE), a chronic inflammatory disease with heterogenous manifestations including lupus nephritis (LN). LN is one of the more severe manifestations of SLE associated
with high morbidity and mortality – risk factors for development of LN include the presence of anti-Smith (Sm) autoantibodies as well as the HLA phenotypes DR3 and DR15, with the
majority of patients typed as DR15. Due to the strong association of LN with a specific autoantigen and HLA DR15 phenotype, it is a good candidate disease for the development of
antigen-specific Tregs for treatment. We first identified DR15-restricted Sm T cell epitopes using a physical affinity binding assay. High-affinity DR15-restricted Sm-specific T cell
receptors were identified using single cell sequencing, then transduced onto primary SLE patient Tregs using lentiviral vectors. In both in vitro co-cultures and in vivo NSG mouse
models of disease using SLE patient PBMCs, our lentivirally-transduced Sm-specific Tregs were significantly better at suppressing Sm-autoreactivity as measured by cell proliferation and
pro-inflammatory cytokines, and nephritis as measured by proteinuria and glomerular segmental necrosis. These results demonstrate that Sm-Treg therapy is a promising treatment for
patients with LN with future potential for use in a clinical setting.