Kamatani Tomoki, Kimura Reiko, Ikeda Satoshi, Inoue Makoto, Seino Ken-Ichiro
Division of Immunobiology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Hokkaido 060-0815, Japan.
Sumitomo Pharma, Co., Ltd., Osaka 541-0045, Japan.
Proc Natl Acad Sci U S A. 2025 Mar 18;122(11):e2413398122. doi: 10.1073/pnas.2413398122. Epub 2025 Mar 12.
Currently, most cell or tissue transplantations using induced pluripotent stem cells (iPSCs) are anticipated to involve allogeneic iPSCs. However, the immunological properties of iPSCs in an allogeneic setting are not well understood. We previously established a mouse transplantation model of MHC-compatible/minor antigen-mismatched combinations, assuming a hypoimmunogenic iPSC-setting. Here, we found that iPSCs subcutaneously inoculated into MHC-compatible allogeneic host mice resisted rejection and formed teratomas without immunosuppressant administration. Notably, when skin grafts were transplanted onto hosts more than 40 d after the initial iPSCs inoculation, only the skin of the same strain as the initial iPSCs was engrafted. Therefore, donor-specific immune tolerance was induced by a single iPSC inoculation. Diverse analyses, including single-cell RNA-sequencing after transplantation, revealed an increase in regulatory T cell (Treg) population, particularly CD25 CD103 effector Tregs within the teratoma and skin grafts. The removal of CD25 or Foxp3 cells suppressed the increase in effector Tregs and disrupted graft acceptance, indicating the importance of these cells in the establishment of immune tolerance. Within the teratoma, we observed an increase in TGF-β2 levels, suggesting an association with the increase in effector Tregs. Our results provide important insights for future applications of allogeneic iPSC-based cell or tissue transplantation.
目前，大多数使用诱导多能干细胞（iPSC）的细胞或组织移植预计将涉及异基因iPSC。然而，在异基因环境中iPSC的免疫学特性尚未得到充分了解。我们之前建立了一种MHC相容/次要抗原错配组合的小鼠移植模型，假设为低免疫原性iPSC环境。在此，我们发现皮下接种到MHC相容的异基因宿主小鼠体内的iPSC在未给予免疫抑制剂的情况下抵抗排斥并形成畸胎瘤。值得注意的是，在初次接种iPSC后40多天将皮肤移植到宿主上时，只有与初次iPSC相同品系的皮肤能够成功移植。因此，单次接种iPSC可诱导供体特异性免疫耐受。包括移植后单细胞RNA测序在内的多种分析表明，调节性T细胞（Treg）群体增加，特别是畸胎瘤和皮肤移植组织中的CD25 CD103效应Treg。去除CD25或Foxp3细胞可抑制效应Treg的增加并破坏移植接受，表明这些细胞在建立免疫耐受中的重要性。在畸胎瘤内，我们观察到TGF-β2水平升高，提示其与效应Treg的增加有关。我们的结果为未来基于异基因iPSC的细胞或组织移植应用提供了重要见解。
