HOXB4-transduced embryonic stem cell-derived Lin-c-kit+ and Lin-Sca-1+ hematopoietic progenitors express H60 and are targeted by NK cells.

Embryonic stem (ES) cells are a novel source of cells, especially hematopoietic progenitor cells that can be used to treat degenerative diseases in humans. However, there is a need to determine how ES cell-derived progenitors are regulated by both the adaptive and innate immune systems post transplantation. In this study, we demonstrate that hematopoietic progenitor cells (HPCs) derived from mouse ES cells ectopically expressing HOXB4 fail to engraft long-term in the presence of NK cells. In particular, the H60-expressing Lin(-)c-kit(+) and Lin(-)Sca-1(+) subpopulations were preferentially deleted in Rag2(-/-), but not in Rag2(-/-)gamma(c)(-/-) mice. Up-regulation of class I expression on HPCs prevented their lysis by NK cells, and Ab-mediated depletion of NK cells restored long-term HPC engraftment. In contrast to the notion that ES-derived cells are immune-privileged, we show in this study that NK cells form a formidable barrier to the long-term engraftment of ES cell-derived hematopoietic progenitors.