Cell Stem Cell. 2024 Jun 06. pii: S1934-5909(24)00181-4. [Epub ahead of print]31(6): 795-802.e6
Hisashi Yano,
Keiko Koga,
Takayuki Sato,
Tokuyuki Shinohara,
Shoichi Iriguchi,
Atsushi Matsuda,
Kazuki Nakazono,
Maki Shioiri,
Yasuyuki Miyake,
Yoshiaki Kassai,
Hitoshi Kiyoi,
Shin Kaneko.
CD4+ T cells induced from human iPSCs (iCD4+ T cells) offer a therapeutic opportunity for overcoming immune pathologies arising from hematopoietic stem cell transplantation. However, most iCD4+ T cells are conventional helper T cells, which secrete inflammatory cytokines. We induced high-level expression of FOXP3, a master transcription factor of regulatory T cells, in iCD4+ T cells. Human iPSC-derived, FOXP3-induced CD4+ T (iCD4+ Treg-like) cells did not secrete inflammatory cytokines upon activation. Moreover, they showed demethylation of the Treg-specific demethylation region, suggesting successful conversion to immunosuppressive iCD4+ Treg-like cells. We further assessed these iCD4+ Treg-like cells for CAR-mediated immunosuppressive ability. HLA-A2 CAR-transduced iCD4+ Treg-like cells inhibited CD8+ cytotoxic T cell (CTL) division in a mixed lymphocyte reaction assay with A2+ allogeneic CTLs and suppressed xenogeneic graft-versus-host disease (GVHD) in NSG mice treated with A2+ human PBMCs. In most cases, these cells suppressed the xenogeneic GvHD progression as much as natural CD25+CD127- Tregs did.
Keywords: graft-versus-host disease; induced pluripotent stem cells; regulatory T cells