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Updated: May 1, 2026
Generation of Natural Killer Cells from Human Expanded Potential Stem Cells
Published on: January 13, 2023
Natural killer cell subsets differentially reject embryonic stem cells based on licensing
Jessica Perez-Cunningham1, Erik Ames, Rachel C Smith
11 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.
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.
Insights
Natural killer (NK) cells reject embryonic stem cells (ESCs). NK cell licensing, particularly via NKG2D, influences this rejection, suggesting its importance for successful stem cell therapies.
Area of Science:
- Immunology
- Stem Cell Biology
- Regenerative Medicine
Background:
- Embryonic stem cells (ESCs) hold therapeutic promise but face immune rejection.
- Natural killer (NK) cells are key immune mediators in stem cell rejection.
- The specific role of NK cell licensing in ESC rejection remains unclear.
Purpose of the Study:
- To investigate the role of NK cells and NK cell licensing in embryonic stem cell (ESC) rejection.
- To identify mechanisms by which NK cells mediate ESC rejection.
Main Methods:
- Cytotoxicity assays using mouse/human ESCs and species-matched NK cells.
- In vivo transplantation of mouse ESCs into allogeneic recipients with NK cell subset depletion.
- Analysis of ESC engraftment using bioluminescent imaging.
- In vitro blocking of NKG2D to assess its role in NK cell-mediated killing.
Main Results:
- Depletion of all NK cells significantly increased ESC engraftment, confirming their role in rejection.
- Differential ESC engraftment observed upon depletion of specific NK cell subsets (Ly49C/I, Ly49G2), highlighting the impact of NK cell licensing.
- Blocking NKG2D reduced NK cell-mediated killing of mouse ESCs, indicating its involvement in the rejection process.
Conclusions:
- Inhibitory Ly49 expression on NK cells correlates with their capacity to kill murine ESCs via an NKG2D-dependent mechanism.
- Licensed NK cells play a critical role in the rejection of allogeneic ESCs.
- The presence of licensed NK cells is likely crucial for the success of stem cell transplantation in humans.
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