NK cell-mediated immune response against tissue/cells regenerated from iPS cells

Abstract

HLA haplotype-homozygous (HLA-homo) induced pluripotent stem cells (iPSCs) are being prepared as a national initiative referred to as the “iPSC Stock Project”, to be used for allogeneic transplantation of regenerated tissue into recipients carrying an identical haplotype in one of the alleles (HLA-hetero). In this article, we address the issue whether NK cells play any roles in graft rejection in this homo-to-hetero transplantation setting, and show our recent finding that NK cells from an HLA-hetero person can kill the cells regenerated from HLA-homo iPSCs when the KIR-ligand is mismatched, by the mechanism of missing-self response. Such cytotoxicity was cancelled when target cells were regenerated from iPSCs transduced with the “missing” HLA gene, providing the basis for an approach to prevent such NK cell-mediated rejection responses. We further discuss the frequency of KIR-ligand mismatch cases occurring in the iPSC Stock Project.