Jessica Perez-Cunningham1, Erik Ames, Rachel C Smith, Anna K Peter, Ridhima Naidu, Jan A Nolta, William J Murphy. 1. 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.
Abstract
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.
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.
Authors: Erik Ames; Robert J Canter; Steven K Grossenbacher; Stephanie Mac; Rachel C Smith; Arta M Monjazeb; Mingyi Chen; William J Murphy Journal: Oncoimmunology Date: 2015-06-05 Impact factor: 8.110
Authors: Trinidad Cisneros; Danielle W Dillard; Xiumei Qu; Justin Arredondo-Guerrero; Martha Castro; Steven Schaffert; Renata Martin; Carlos O Esquivel; Sheri M Krams; Olivia M Martinez Journal: Am J Transplant Date: 2019-01-16 Impact factor: 8.086
Authors: Ratnesh Singh; Oscar Cuzzani; François Binette; Hal Sternberg; Michael D West; Igor O Nasonkin Journal: Stem Cell Rev Rep Date: 2018-08 Impact factor: 5.739