Human and mouse natural killer cell cytotoxicity towards embryonic stem cells (169.41)

Abstract Embryonic stem cells (ESC) have tremendous potential for the treatment of numerous diseases but little is known regarding the immune response towards them. Human ESC (hESC) express very low levels of MHC class I, rendering them resistant to T cell-mediated rejection but making them likely targets of natural killer (NK) cells. As clinical use of MHC-matched ESC is unlikely, we examined the susceptibility of ESC to NK cell mediated killing. We tested the ability of activated human NK cells from several different donors to lyse the H9 hES cell line in vitro. Activated peripheral blood NK cells achieved significant H9 killing in a 4 hour chromium release assay. Similar experiments using mouse ES cell lines (JM8A3.N1, B6 background) with syngeneic (B6) or allogeneic (BALB/c) activated NK effector cells showed significant mouse ESC killing, regardless of NK cell source. This could be explained by very low MHC class I expression on the ESC targets leading to NK cell-mediated lysis due to lack of MHC class I, rather than allogeneic recognition. Experiments determining mouse ESC in vivo clearance by NK cells are under way. Together these data underscore the susceptibility of human and mouse ESC to NK cell-mediated lysis. This suggests that therapeutic applications of ESC are susceptible to host NK-cell mediated resistance.