HOXB4-Transduced Embryonic Stem Cell-Derived Lin−c-kit+ and Lin−Sca-1+ Hematopoietic Progenitors Express H60 and Are Targeted by NK Cells

Abstract

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−/−γc−/− 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.

Immunobiology of naïve and genetically modified HLA-class-I-knockdown human embryonic stem cells

“…The in vivo NK activity was found to be increased and the frequency of teratoma formation significantly reduced (Dressel et al, 2010). In vivo rejection of murine ESC derivatives by NK cells has also been reported in Rag2 -/-mice (Tabayoyong et al, 2009). Both mouse models lack functional lymphocytes and contain greatly increased numbers of NK cells (Tabayoyong et al, 2009).…”

“…In vivo rejection of murine ESC derivatives by NK cells has also been reported in Rag2 -/-mice (Tabayoyong et al, 2009). Both mouse models lack functional lymphocytes and contain greatly increased numbers of NK cells (Tabayoyong et al, 2009). The impact of NK cells in immunocompetent hosts might, however, be less important.…”

Human iPS cell–derived hematopoietic progenitor cells induce T-cell anergy in in vitro–generated alloreactive CD8+ T cells

“…These CTLs were used as effector cells, whereas iPS-HPCs, M23e immortalized B cells, and M28e cells were used as target cells in 4-hour 51 Cr-release assay, as described previously. 25 …”

“…Indeed, our studies recently showed that NK cells regulated the engraftment of mouse ESC-HPCs. 25 Here, we studied the MHC expression by iPS-HPCs, iPSCs, and the parental fibroblasts. ESCs, ESC-HPCs, and UCB-CD34 1 cells…”

“…This observation supports our own studies on ESC-HPCs in which we showed HPCs to be highly susceptible to NK cells in vivo but not in vitro. 25 More recently, it was reported that mouse iPSCs were rejected in syngeneic mice, whereas ESCs were not, suggesting that iPSCs are potentially immunogenic. 26 This clearly demonstrates the importance of defining the immunologic properties of iPSC derivatives to allow determination of their potential clinical application.…”