HEMATOPOIETIC-CELLS AND RADIORESISTANT HOST ELEMENTS INFLUENCE NATURAL-KILLER-CELL DIFFERENTIATION

Radioresistant host elements mediate positive selection of developing thymocytes, whereas bone marrow-derived cells induce clonal deletion o f T cells with receptors that are strongly autoreactive. In contrast t o T cell development, little is known about the elements governing the natural killer (NK) cell repertoire, which, similar to the T cell rep ertoire, differs between individuals bearing different major histocomp atibility complex (MHC) phenotypes. We have used murine bone marrow tr ansplantation models to analyze the influence of donor and host MHC on an NK cell subset. We examined the expression of Ly-49, which is stro ngly expressed on a subpopulation of NK cells of H-2b mice, but not by NK cells of H-2a mice, probably because of a negative effect induced by the interaction of Ly-49 with D(d). To evaluate the effect of hemat opoietic cell H-2a expression on Ly-49 expression of H-2b NK cells, we prepared mixed allogeneic chimeras by administering T cell-depleted a llogeneic (B10.A, H-2a) and host-type (B10, H-2b) marrow to lethally i rradiated B10 mice, or by administering B10.A marrow to B10 recipients conditioned by a nonmyeloablative regimen. Expression of H-2a on bone marrow-derived cells was sufficient to downregulate Ly-49 expression on both H-2a and H-2b NK cells. This downregulation was thymus indepen dent. To examine the effect of H-2a expressed only on radioresistant h ost elements, we prepared fully allogeneic chimeras by administering B 10 bone marrow to lethally irradiated B10.A recipients. B10 NK cells o f these fully allogeneic chimeras also showed downregulation of Ly-49 expression. The lower level of H-2a expressed on H-2b x H-2a F1 cells induced more marked downregulation of Ly-49 expression on B10 NK cells when presented on donor marrow in mixed chimeras than when expressed only on radioresistant host cells. Our studies show that differentiati on of NK cells is determined by interactions with MHC molecules expres sed on bone marrow-derived cells and, to a lesser extent, by MHC antig ens expressed on radioresistant host elements.