Autoantigen-specific regulatory t cells halt the progression of lupus nephritis
Cytotherapy(2024)
Abstract
Background & Aim
Regulatory T cells (Tregs) are crucial for maintaining immune homeostasis and preventing autoimmunity. Previous studies show autoantigen-specific Tregs potently and specifically suppress autoimmunity, indicating their potential to be engineered as a cell-based therapy for autoimmune diseases. Systemic lupus erythematosus (SLE) and its more severe manifestation, lupus nephritis (LN) are associated with auto-reactivity to the Smith (Sm) antigen and HLA-linked to DR15. Here we develop Sm-specific Tregs as a potential cell-based therapy for LN.
Methods, Results & Conclusion
We identified immunodominant DR15-restricted Sm T cell epitopes using an affinity binding assay and T cell proliferation assay. T cell receptors (TCRs) specific for Sm epitopes were identified by co-culturing CD4+ T cells with Sm-peptide-pulsed DR15+ dendritic cells, and sequencing the proliferated CD4+ T cells by 10X single-cell sequencing. TCRs were ranked based on clonal expansion and apparent affinity. TCR candidates were engineered into a lentiviral vector and transduced onto primary DR15+ SLE patient Tregs or healthy donor Tregs (Sm-Tregs). Sm-Tregs were assessed for suppression of T effector cell function in vitro and in a humanised model of LN.Three immunodominant Sm epitopes were identified; SmB/B’1-15, SmB/B’58-72, and SmD343-57. SmB/B’58-72 showed the highest binding to DR15 and immunogenicity by CD4+ T cell proliferation. To generate Sm-Tregs, a SmB/B’58-72- specific TCR was lentivirally transduced onto Tregs. In vitro suppression assay revealed Sm-Tregs were 5.33 times more suppressive of Sm-Tconv proliferation than polyclonal Tregs. Co-cultures of SLE patient PBMCs with SmB/B’58-72 revealed Sm-Tregs, but not polyclonal Tregs induced 90% suppression of IFN-γ whereas Sm-Tregs produced significantly more IL-10 (p<0.01). Transfer of Sm+ DR15+ SLE patient PBMCs into NSG-MHCnull mice but not healthy control PBMCs, induced proteinuria and renal injury characteristic of LN. Treatment with Sm-Tregs halted the progression of functional and histological injury.Sm-Tregs engineered to target an immunodominant Sm epitope potently suppressed Sm-specific T effector responses. A humanised mouse model of LN showed Sm-Tregs were superior to polyclonal Tregs in halting disease progression. Autologous Sm-Treg therapy is a promising cell-based therapy for the treatment of LN, and sets a premise for autoantigen-specific Tregs for the treatment of other autoimmune conditions.
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Key words
Lupus,Treg,TCR
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