Inhibition of bone marrow colony formation by human natural killer cells and by natural killer cell-derived colony-inhibiting activity.

Abstract

Incubation of human peripheral blood lymphocytes with bone marrow cells resulted in significant inhibition of colony formation by committed myeloid and erythroid cells. Using positively selected homogeneous natural killer (NK) cell preparations and lymphocyte subpopulations depleted of or enriched for NK cells, we definitively characterize as NK cells the cells in normal peripheral blood that are responsible for inhibition of bone marrow colony growth. The inhibitory effect of NK cells on hematopoiesis can be mediated by a soluble factor that is produced only by NK cells upon culture with HLA-DR+ hematopoietic cells and with NK-sensitive cell lines. Both NK cells and the NK-produced, colony-inhibiting activity (NK-CIA) are suppressive for allogeneic and autologous bone marrow CFU-GEMM (colony-forming units, granulocyte, erythroid, monocyte, megakaryocyte), CFU-E (CFU, erythroid), and early CFU-GM (CFU, granulocyte, monocyte), but not for either BFU-E (burst-forming units, erythroid) or late CFU-GM. [3H]Thymidine incorporation was inhibited by NK-CIA-containing supernatants in HLA-DR+ but not HLA-DR- bone marrow cell populations stimulated to proliferative by colony-stimulating factor (CSF). These data suggest that the NK cell-mediated inhibitory effect on proliferation and differentiation of hematopoietic precursor cells is mediated in part or completely by the secreted NK-CIA. The concentration of NK-CIA reached in the supernatant of the mixture of NK cell-containing lymphocyte populations with bone marrow cells is sufficient to account for the inhibitory effect mediated by NK cells. Our data support the hypothesis that human NK cells play a major role in the control of hematopoiesis, down-regulating it under conditions in which the NK cells are functionally activated.

Biology of Natural Killer Cells

“…The inhibitor cells were resistant to 10 Gy irradiation but required several hours of contact with the bone marrow cells before plating in semisolid medium, in order to mediate maximum inhibition (936). Bone marrow-derived CFU-GMs and erythrocyte CFUs (CFU-Es) are maximally inhibited by NK cells (668,(934)(935)(936)(937)(938)(939), whereas inhibition of erythrocyte burst-forming units (BFU-Es) was observed in only one study (939) using HNK-l/Leu-7+ cells. Two studies have shown that peripheral blood-derived CFU-GMs are not inhibited, but rather are stimulated by NK cells (122,940).…”

“…Degliantoni et al (668,938) showed that the peripheral blood cells that spontaneously suppress bone marrow hematopoietic colonies have the exact phenotype of NK cells (i.e., CD16+, NKH-l+, CD3-, CD5-, CD4-, HLA-DR-, mostly CD2+, and, in part, CD8+ and HNK-I+). The suppressive effect of these cells was increased by pretreatment with IFN-a.…”

Homeostatic and pathogenic extramedullary hematopoiesis

“…This study, however, did not determine if the increase was the outcome of cell mobilization from the bone marrow or the product of the EH in the spleen. In vitro , NK cells can conversely decrease the numbers of progenitor cells 32,33. While the mechanism remains to be determined, NK cells could perhaps regulate the hematopoiesis with soluble inhibitory factors or through their cell-killing activity.…”

Chronic natural killer cell lymphocytosis

“…[19][20] Furthermore, clonally different populations of NK cells may specifically affect either myelopoiesis or erythropoiesis.I* These observations potentially may explain the variable degrees of cytopenias seen in patients with CNKL. The response to immunosuppressive therapy associated with decreases in the NK cell population is consistent with the aforementioned pathogenetic mechanisms.…”