Global unresponsiveness as a mechanism of natural killer cell tolerance in mixed xenogeneic chimeras.

Mixed xenogeneic chimerism induces T- and B-cell tolerance in mice receiving T-cell-depleted rat bone marrow cells (BMC) following nonmyeloablative conditioning that includes alphabeta and gammadelta T cell and Natural killer (NK) cell-depleting mAbs. NK-cell depletion is essential to permit marrow engraftment, but NK-cell tolerance has not been previously assessed in mixed xenogeneic chimeras. We assessed NK-cell tolerance in rat --> mouse mixed xenogeneic chimeras using in vivo(125)I-5iodo-2-deoxyuridine assays. Additional rapid marrow rejection mechanisms resulted in a requirement for 10-fold more rat than ss2 microglobulin knockout (ss2M(-/-)) (MHC class I-deficient) mouse BMC to achieve engraftment in NK-cell-depleted mice. Both 12-week mixed xenogeneic chimeras and conditioned controls showed reduced resistance to engraftment of ss2M(-/-) mouse and rat BMC. While conditioned control mice recovered NK-cell-mediated resistance to ss2M(-/-) and rat BMC by 16 weeks, mixed chimeras lacked resistance to either, similar to NK-cell-deficient Ly49A transgenic mice. Thus, global NK-cell unresponsiveness is induced by mixed xenogeneic chimerism. Our data suggest that NK-cell anergy is induced by interactions with xenogeneic hematopoietic cells that express activating but not inhibitory ligands for recipient NK cells.