Inhibition of pluripotent hematopoietic stem cells of bone marrow by large granular lymphocytes.

Abstract

Previous studies suggested that natural killer (NK) cells are involved in the regulation of the growth and differentiation of pluripotent hematopoietic stem cells. To establish whether the effector cells responsible for the in vivo resistance to bone marrow (BM) transplants and the in vito inhibition of colony-forming units (CFU) may represent identical or overlapping populations, we used a rat system for syngeneic BM transplantation, with and without the transfer of large numbers of peripheral blood large granular lymphocytes (LGLs). BM reconstitution was measured by the in vivo formation of syngeneic CFU in the spleen (CFU-s). Because of the very low frequency of CFU-s in normal rat BM, we fractionated BM cells in Percoll density gradients, which provided a 2-to 5-fold enrichment in CFU-s in the lowerdensity fractions. Although these fractions contained <10% of the total cells, they contained >75% of the CFU-s and allowed for the transfer of significantly fewer donor cells. At the time of BM transplantation, radiation-resistant asialoganglioside GM1-positive LGLs, with high NK activity, accounted for a significant percentage of the lymphoid cells in the irradiated recipient. The in vivo regulatory role of these cells on engraftment was demonstrated by their depletion (by i.v. injection of small amounts of anti-asialo-GM1 antiserum before BM transplantation), which resulted in a significant increase in the number of CFU-s. Conversely, a 50% inhibition in CFU-s was found when CFU-s-enriched BM fractions were preincubated in vitro with LGLs. Additional experiments, involving selective in vivo depletion of NK cells followed by LGL repopulation, directly demonstrated the involvement of LGLs in the regulation and growth of syngeneic pluripotent hematopoietic stem cells. Our results further support the hypothesis that LGLs are involved directly or via humoral factors in the homeostasis and regulation of hematopoietic stem cell growth and differentiation.

Deregulated TCRαβ T cell population provokes extramedullary hematopoiesis in mice deficient in the common γ chain

“…However, we consider an intrinsic defect in y; HSC differentiation unlikely, since y; fetal liver hematopoiesis and adult y,-IRAG2-'-hematopoiesis were normal. Similarly, the enhanced hematopoiesis observed in y; mice does not appear to be due to the absence of NK cells, which have been proposed as negative regulators of hematopoiesis, either through direct cytotoxicity towards HSC or through the elaboration of suppressive cytokines [19,20]. The elimination of NK cells from RAG2-I-mice had no enhancing effect on hematopoiesis, effectively ruling out a major contribution of NK cells in this process.…”

“…Mature lymphocytes have been shown to influence hematopoiesis, potentially through direct cellular interactions with the HSC [19]. NK cells in particular have been suggested to play a negative role in HSC differentiation [20].…”

Natural Killer Cells and Recognition of MHC Class I Molecules: New Perspectives and Challenges in Immunology

“…tumors in vivo [169], although a role for NK cells in the elimination of primary tumors in vivo has not been shown. NK cells have furthermore been implicated in the control of normal hematopoiesis [170,171]. Furthermore, their recognition of MHC class I mismatches of hematopoietic target cells [37,63,[172][173][174] has aroused interest in these cells as potential obstacles to successful bone marrow allotransplantation [37,49,63,[174][175][176].…”

Autologous Bone Marrow Purging by Lymphokine-Activated Killer Cells: Rationale and Prospects

“…There are con siderable data in the literature concerning BM stem cell progenitor inhibition by natu ral killer cells [28][29][30]. Accumulated evi dence indicates that LAK cells suppress var ious progenitors.…”