Transplantation of pancreatic islets or β cells has been shown to be a potential cure for T1D, but the shortage of donor organs limits the availability of this therapy. Induced pluripotent stem cells (iPSCs) hold great promise as a source of pancreatic β cells for cell therapy because they can differentiate into virtually any cell type in the body, including β cells. However, the immune response limits the use of autologous cell engraftment, while transplantation of allogeneic iPSC pancreatic derivatives leads to CD8+ T cell-mediated allograft rejection.

To overcome this problem, researchers have explored various strategies to make iPSC-derived cells less visible to the immune system. One strategy involves using MHC-I-/- iPSCs, which lack the major histocompatibility complex class I (MHC-I) molecules that present antigens to CD8+ T cells. However, this strategy may trigger missing-self recognition by natural killer (NK) cells, which can recognize cells that lack MHC-I molecules.

Recent studies have shown that two immune checkpoints, B7-H3 and CD155, are highly expressed in iPSC-derived pancreatic progenitors (iPPs) and function as NK cell activating receptor ligands. Therefore, researchers used CRISPR/Cas9 technology to generate MHC-I-deprived B7H3-/-/CD155-/- iPPs and tested their ability to evade NK response in vivo. The engineered iPPs were transplanted into humanized mice alongside wild-type (WT) and MHC-I-/- iPPs.

The results showed that MHC-I-/-/B7H3-/-/CD155-/- cells evaded immune recognition in vivo, similar to WT cells. The higher survival rate of the engineered cells correlated with improved maturation capacity of the endocrine progenitors, resulting in a significantly higher number of insulin-secreting β cells than the MHC-I-/- iPPs.

This study suggests that NK activating receptor ligands could be used as novel targets to make grafts invisible to immune cell recognition in vivo, offering new possibilities for using clinical-grade iPSC pancreatic derivatives as next-generation cell therapy for T1D treatment. These findings could be significant in enhancing the effectiveness of iPSC-derived cell therapies for T1D and may have implications for the development of cell therapies for other autoimmune diseases as well.

In conclusion, the use of iPSCs as a source of pancreatic β cells for T1D therapy holds great promise, but the immune response limits their effectiveness. The strategy of using MHC-I-/- iPSCs has been explored, but it may trigger NK cell recognition. The present study offers a new approach by using CRISPR/Cas9 technology to generate MHC-I-deprived B7H3-/-/CD155-/- iPPs that evade immune recognition in vivo. This strategy could enhance the effectiveness of iPSC-derived cell therapies for T1D and other autoimmune diseases.