iPSC-Derived Regulatory Dendritic Cells Inhibit Allograft Rejection by Generating Alloantigen-Specific Regulatory T Cells

Abstract

Regulatory dendritic cell (DCregs)-based immunotherapy is a potential therapeutic tool for transplant rejection. We generated DCregs from murine induced pluripotent stem cells (iPSCs), which could remain in a "stable immature stage" even under strong stimulation. Harnessing this characteristic, we hypothesized that iPS-DCregs worked as a negative vaccine to generate regulatory T cells (Tregs), and induced donor-specific allograft acceptance. We immunized naive CBA (H-2K^k) mice with B6 (H-2K^b) iPS-DCregs and found that Tregs (CD4⁺CD25⁺FOXP3⁺) significantly increased in CBA splenocytes. Moreover, immunized CBA recipients permanently accepted B6 cardiac grafts in a donor-specific pattern. We demonstrated mechanistically that donor-type iPS-DCregs triggered transforming growth factor β1 secretion, under which the donor-antigen peptides directed naive CD4⁺ T cells to differentiate into donor-specific FOXP3⁺ Tregs instead of into effector T cells in vivo. These findings highlight the potential of iPS-DCregs as a key cell therapy resource in clinical transplantation.

Keywords: TGF-β1; antigen-specific tolerance; iPSC; murine cardiac allotransplant; regulatory T cells; regulatory dendritic cells.