Natural killer cell subsets differentially reject embryonic stem cells based on licensing.
BACKGROUND
Embryonic stem cells (ESC) and induced pluripotent stem cells provide great promise to the future of medicine. Because immune rejection represents a major obstacle to the success of all stem cell-based therapies, many recent studies have sought to determine the key immune mediators involved in ESC rejection. The role of natural killer (NK) cells and specifically the role of NK cell licensing is not well understood in ESC rejection.


METHODS
Mouse or human ESCs were subjected to cytotoxicity assays involving their respective species-matched activated NK cells. Mouse ESCs were then transplanted to allogeneic recipients after depletion of NK cell subsets in the host. ESC engraftment was analyzed by bioluminescent imaging.


RESULTS
Depletion of all NK cells in vivo resulted in the greatest amount of ESC engraftment, confirming a role for NK cells in ESC rejection. Importantly, depletion of the Ly49C/I or Ly49G2 NK cell subsets resulted in differential ESC engraftment and rejection. This indicates that NK cell rejection of allogeneic ESC is highly differential based on the presence of licensed NK cells. Blocking NKG2D in vitro resulted in less killing of mESC by allogeneic NK cells, indicating NKG2D is a likely mechanism for NK-mediated killing of mESC.


CONCLUSIONS
In this study, we show that expression of inhibitory Ly49s correlates with the ability of NK cells to kill murine ESC in an NKG2D-dependent manner. This further suggests that the rejection of similar stem cell transplants in humans will be dependent upon the presence of licensed NK cells.
1 Department of Dermatology, School of Medicine, University of California, Davis, Sacramento, CA. 2 Department of Internal Medicine, School of Medicine, University of California, Davis, Sacramento, CA. 3 Stem Cell Program and Institute for Regenerative Cures, University of California, Davis, Sacramento, CA. 4 Address correspondence to: William J. Murphy, Ph.D., Department of Dermatology, University of California, Davis School of Medicine, IRC-Suite 1630, 2921 Stockton Blvd. Sacramento, CA 95817.
Jessica
J
Perez-Cunningham
Erik
E
Ames
Rachel C
RC
Smith
Anna K
AK
Peter
Ridhima
R
Naidu
Jan A
JA
Nolta
William J
WJ
Murphy
D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D053595:Embryonic Stem Cells / Q000276:immunology*; D006084:Graft Rejection / Q000276:immunology* / Q000473:pathology; D006801:Humans; D007111:Immunity, Cellular; D007694:Killer Cells, Natural / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D033581:Stem Cell Transplantation; D014184:Transplantation, Homologous