Low number of H-2Dd-negative haematopoietic cells in mixed bone marrow chimeras convey in vivo tolerance to H-2Dd-negative cells but fail to prevent resistance to H-2Dd-negative leukaemia

Natural killer (NK) cells kill cells lacking self major histocompatibility complex (MHC) class I. This missing self reactivity is beneficial in haploidentical bone marrow transplantations to cure leukaemia, in which donor-derived NK cells reject MHC disparate leukaemia cells and prevent relapse. To understand the role of NK cells in transplantation, we have studied NK cell tolerance in mice receiving mixed bone marrow transplants with limiting number of the MHC disparate component. Using an MHC class I (D-d) transgenic mouse model, we generated bone marrow chimeras carrying mixtures of D-d-positive and -negative cells. NK reactivity against D-d-negative cells (missing self) was assayed by outgrowth of lymphoma cells, stability of the chimerism in vivo and killing of Concanavalin A blasts in vitro. Up to 20% D-d-negative haematopoietic cells reduced, but did not abrogate, rejection of D-d-negative tumours and killing of D-d-negative T-cell blasts. In contrast, the ratios between D-d-positive and -negative cells were stable in vivo, suggesting tolerance to normal cells. Our data suggest that NK cell tolerance to normal cells and tumours in mixed MHC environments is differentially regulated, tolerance to normal cells being more easily induced. These results are important in relation to the role of NK cells in antileukaemic reactions after bone marrow transplantation.