Natural killer cells weakly resist engraftment of allogeneic, long-term, multilineage-repopulating hematopoietic stem cells.

Natural killer (NK) cells effect hybrid resistance, in which parental hematopoietic cell grafts are rejected by F1 recipients. NK cells can also resist engraftment of fully MHC-mismatched allogeneic marrow. However, studies of NK cell-mediated alloresistance have relied on short-term proliferation, colony, or survival assays; therefore, their results may not reflect effects of NK cells on the engraftment of allogeneic pluripotent hematopoietic stem cells (PHSC). We have now addressed the role of NK cells in resisting engraftment of these most primitive hematopoietic cells, which provide long-term repopulation of multiple hematopoietic lineages. We took advantage of a nonmyeloablative conditioning regimen that permits allogeneic marrow engraftment and induction of mixed chimerism in mice to evaluate the effect of host NK cell depletion with mAb PK136 on long-term competitive repopulating ability of allogeneic marrow. Mice were pretreated with depleting anti-CD4 and anti-CD8 mAbs, then received 3 Gy of whole body irradiation and 7 Gy of thymic irradiation prior to allogeneic bone marrow transplantation. Depending on the strain combination used, statistically significant increases in long-term allogeneic repopulation of both myeloid and lymphoid cell lineages were observed in recipients depleted of NK cells before bone marrow transplantation compared with controls. Depletion of host NK cells alone was sufficient to enhance donor PHSC engraftment. However, a statistically significant increase in allogeneic reconstitution in NK cell-depleted chimeras compared with control chimeras was not observed in every experiment, and differences were most readily apparent in a strain combination in which recipient NK cells have been shown to have high resistance to engraftment of donor short-term repopulating cells. Chronic (16 weeks) anti-NK1.1 treatment resulted in higher levels of donor-type repopulation than that in animals receiving only pretransplant NK cell depletion. Our studies demonstrate for the first time that host NK cells resist engraftment of allogeneic long-term repopulating PHSC, and provide a model for studying the elements that determine what is regarded as "self" and "non-self" by newly developing NK cells.