Stem cell-derived tissue-associated regulatory T cells ameliorate the development of autoimmunity

Abstract

Pluripotent stem cells (PSCs) have the potential to produce almost all of the cells in the body, including regulatory T cells (T regs). However, the exact conditions required for the development of antigen (Ag)-specific T regs from PSCs (i.e., PSC-T regs) are not well delineated. Ag-specific PSC-T regs can be tissue/organ-associated and migrate to local inflamed tissues/organs to suppress the autoimmune response after adoptive transfer, thereby avoiding potential overall immunosuppression from non-specific T regs. In this study, we developed a new approach to generate functional Ag-specific T regs from induced PSCs (iPSCs), i.e., iPSC-T regs, which had the ability to generate an Ag-specific immunosuppressive response in a murine model of arthritis. We retrovirally transduced murine iPSCs with a construct containing genes of Ag-specific T cell receptor (TCR) and the transcriptional factor FoxP3. We differentiated the iPSCs into Ag-specific iPSC-T regs using in vitro or in vivo Notch signaling, and demonstrated that adoptive transfer of such T regs dramatically suppressed autoimmunity in a well-established Ag-induced arthritis model, including the inflammation, joint destruction, cartilage prostaglandin depletion, osteoclast activity, and Th17 production. Our results indicate that PSCs can be used to develop Ag-specific T regs, which have a therapeutic potential for T reg-based therapies of autoimmune disorders.