Characterization of a subset of bone marrow-derived natural killer cells that regulates T cell activation in rats (original) (raw)
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Natural killer cells and nitric oxide
International Immunopharmacology, 2001
Ž. Ž. Natural killer NK cells and nitric oxide NO are both important components of the natural or innate immune response. NK cells are large granular lymphocytes capable of destroying cells infected by virus or bacteria and susceptible tumor cells without prior sensitization and restriction by MHC antigens. They are abundant in blood, spleen, liver and lungs and are distinct from both T and B lymphocytes in their circulation patterns, profile of surface antigens, receptor repertoire and the way in which they discriminate between self and non-self. Uniquely, NK cells express receptors that can recognize and discriminate between normal and altered MHC class I determinants. NK cell cytotoxic activity is strongly induced by cytokines such as IL-2 and IL-12, and this activation is associated with synthesis of NO. Inhibitors of NO synthesis impair NK cell-mediated target cell killing, demonstrating a role for NO in NK cell function. Furthermore, NO itself can regulate NK cell activation. In this article, evidence that NO is a mediator of NK cell-mediated target cell killing, and that NO is a regulator of NK cell activation will be reviewed. Results of NO synthase gene deletion studies will be discussed, and rodent and human NK cells will be compared.
Cellular Immunology, 1989
The coculture of rat bone marrow cells with recombinant interleukin-2 induced the generation of cells mediating natural killer (NK) activity and subsequent lymphokine-activated killer (LAK) activity depending upon the dose of IL-2 and time of culture. NK activity was detected as early as 4 to 5 days after the addition of IL-2 and could be evoked with as little as 5 to 50 U/ ml. The induced NK cells had large granular lymphocyte (LGL) morphology and expressed OX8 and asialo GM, surface markers but did not express OX19 or W3/25 markers. LAK activity was detected only after 5 days of culture, and required above 100 U/ml IL-2. Cells mediating LAK activity also expressed OX8 and asialo GM, but not OX 19. The generation of detectable NK and subsequent LAK activity was due to induction of early progenitor cells and not contaminating mature LGL/NK cells within the bone marrow population since of removal of such mature NK cells with L-leucine methyl ester (L-LME) did not aliect the subsequent generation of either activity. Moreover, the removal of actively dividing cells as well as mature NK cells from the bone marrow by treatment with 5-fluorouracil(5FU) in vivo enriched the remaining bone marrow population for both NK and LAK progenitor cells. The phenotype of the L-LME-and 5-FU-resistant NK and LAK progenitor cells within populations of bone marrow was determined by antibody plus complement depletion analysis. Although treatment of normal bone marrow with anti-asialo GM, + C reduced the induction of NK and LAK activity in 5-day cultures, treatment of 5-FU marrow with anti-asialo GM, + C did not affect either activity. Treatment with a pan-T cell antibody + C did not affect the development of NK or LAK activity under any conditions. Thus, the 5-FU-resistant NK/LAK progenitors were asialo GM, negative but became asialo GM: after induction by IG2. Finally, evidence that bone marrow-derived LAK cells were generated directly from the IL-2-induced NK cells was obtained by treating the IL-2induced LGL/NK cells with L-LME. This eliminated the induced NK activity as well as the capacity of the remaining bone marrow cells to generate LAK activity. Thus, in rat bone marrow, NK cells appear to be derived from asialo GM;, OX 19-, nongranular, 5-FU-and L-LMEresistant progenitor cells which can be induced to generate LGL with NK activity with low levels of IL-2.
Biology of Blood and Marrow Transplantation, 2004
shown that natural killer (NK) cells from PBPC collections are less expandable in vitro than those obtained during steady-state hematopoiesis. We show here that the extent of this proliferation deficit is related to the number of circulating CD34 ؉ cells in vivo at the time of PBPC apheresis. Likewise, addition of autologous CD34 ؉ cells to unseparated PBL reduced the expansion of the NK-cell subset by 22.2% ؎ 6.0% (n ؍ 10; P <.005). In contrast, when using purified NK cells, their proliferation remained unimpaired by autologous CD34 ؉ cells. Supernatants from CD34 ؉ cells cultured with autologous PBLs had an inhibitory effect on proliferation of purified NK cells (n ؍ 16; P ؍ .03), indicating that an interaction between CD34 ؉ cells and lymphocytes is essential for the suppressive effect on NK cells. To investigate the role of T cells in this interaction, intracellular cytokines were determined in T cells cultured for 7 days with or without autologous CD34 ؉ cells. When cultured with CD34 ؉ cells, the frequency of IL-2-producing CD4 ؉ and CD8 ؉ T cells was reduced by 19% and 24%, respectively, compared with T cells cultured alone (n ؍ 7; P ؍ .016). Interferon-␥-producing T cells were slightly reduced (P ؍ not statistically significant [ns]). Finally, the influence of T cells and NK cells on the recovery of myeloid colony-forming cells (CFU-GMs) from purified CD34 ؉ cells was examined. In the presence of T cells, 16% ؎ 6% of the input CFU-GM recovered after 7 days, compared with 5% ؎ 4% in the presence of NK cells (n ؍ 5; P ؍ ns). Our findings point to an inhibition of NK-cell proliferation mediated by an interaction of CD34 ؉ cells and T cells occurring during PBPC mobilization with G-CSF.
In Vivo Generation of Mouse Natural Killer Cells: Role of the Spleen and Thymus
Scandinavian Journal of Immunology, 1978
The role of the spleen and thymus was investigated in the natural killer {NK) cell system. These NK cells have the ability to kill a variety of tumour cells as demonstraled in vitro in short-term '*Cr release assays. The work presented deals with three observations: (1) the effect of splenectomy on the levels of NK aclivily in the blood and lymph nodes. (2) ihe elTeci of splenectomy on the reconstitution of irradiated animals with hone marrow cells, and (.1) the kvel of NK aetivity in adult ihymectomized. irradiated animals which were reconsiituted with bone marrow or thymus cells from either high or low NK activity animals. Thus, for the third point, chimaeras were established between histocompaiible strains of miee A.BY (a low NK strain), and C57BI/6 (a high NK strain). The ability of T cells from one strain could then be observed lo eilher help or suppress the NK activity of the bone-marrow-derived cells. The daia presented show that the absence of a spleen does not affect NK activity or reconstitution of N K cells in irradiated animals. Further, T eells from one strain do not affect NK activity of animals rcconstiluled with bone marrow eells from a histoconipatible strain. Thus T cells from a low NK. stain (A.BY) did not suppress the high activity of C57B1/6 cells, and. conversely, the C57BI/6 T cells did not competisate for the low NK activity of A.BY cells.
Growth of Murine Natural-Killer-Cells from Bone-Marrow Invitro - Role of TNF-Alpha and Ifn-Gamma
International Journal of Immunopharmacology, 1991
It has been previously shown that natural killer (NK) cell growth can be induced by interleukin-2 (IL-2) in bone marrow (BM) cultures and that other cytokines (CKs), including IL-la, act synergistically with IL-2. However, as the effect of IL-2 and IL-la could be due to direct stimulation of NK progenitor cell growth, as well as to the induction of other factors, we analysed the role of the endogenous production of CKs in BM cultures. Results show that mRNAs specific for tumour necrosis factor-a (TNFa) and interferongamma (IFNy) are detectable within hours in BM cultures supplemented with IL-2 and IL-la, and that the amount is higher when both IL-2 and IL-la are present. Antibodies directed against TNFa and IFNy abrogate the NK cell development, indicating that these CKs play an essential role. The antibodies, however, had no effect on mature NK cells. Furthermore, pretreatment of BM cells with TNFa or IFNy before culturing with IL-2, enhances IL-2 responsiveness and NK cell growth. These results suggest that induction of cytokines production may be important for growth of NK cells from BM precursors and that the synergistic effect of IL-I~ could be due, at least in part, to increased TNFa and IFNy production. Interleukin-2 and IFNs have been shown to stimulate the in vivo and in vitro growth of NK cells in both man and animals (
Characterization of natural killer cells and their precursors in the murine bone marrow
Cellular Immunology, 1986
We have fractionated murine bone marrow cells according to their density on bovine serum albumin (BSA) gradient and studied (a) the NK activity against YAC-1 targets, (b) the proportion of asialo GMl+ lymphocytes, (c) and the presence of large granular lymphocytes (LGL) in the different fractions (A, B, C, D). The NK activity was found mainly in the C fraction, but the proportion of asialo GM l+ cells was the same in every fraction. No LGLs were found in the bone marrow. Cells from the various fractions were also transplanted into irradiated recipients. Seven days later the highest NK activity was found in the spleens of mice injected with cells from the A + B fractions indicating that the immediate precursors for NK cells reside in the low density fractions of the BSA gradient. Mice transplanted with C or D fractions needed longer time to develop normal NK levels. The treatment of bone marrow cells before transplantation with antiasialo GM 1 + complement did not inhibit the development of NK activity, so it can be concluded that the precursor for NK is asialo GM le. 0 1986 Academic press, IIIC.
Natural killer cell precursors in the CD44neg/dim T-cell receptor population of mouse bone marrow
Blood, 1996
Natural killer (NK) cells develop from the nonadherent cell component of NK long-term bone marrow (BM) cultures (NK-LTBMC). Because these nonadherent cells are depleted of mature NK cells and T cells, but appear to enriched for NK precursors, they were used as a starting population to begin to define the NK precursors that function in NK- LTBMC. As the stromal cell component of NK-LTBMC has been shown to support interleukin (IL)-2-induced, CD44 dependent, NK cell development from nonadherent NK precursors, NK-LTBMC stroma was used in a limiting dilution assay (LDA) to quantitate the precursors. NK-LTBMC in 96-well plates were irradiated (20 Gy) to kill hematopoietic cells (including the NK precursors), seeded with limiting dilutions of the cells to be quantitated, cultured with 500 U/mL IL-2 for 13 days and assayed for development of NK activity by adding 51Cr-labeled YAC-1 cells to the wells and evaluating the release of 51Cr after 4 hours. Flow cytometric analysis, sorting, and qu...
1992
We have previously shown that interleukin-2 (IL-2) is able to induce the generation of natural killer (NK) activity in bone marrow (BM) cell cultures from mice pretreated with Huorouracil (5FU). Cell fractionation experiments to analyze the nature of BM precursors indicate that MAC-I-, NKI -1 -noncytotoxic precursors are induced by IL-2 to proliferate and generate cytolytic NK cells. These data demonstrate that the phenotype and functional characteristics of the IL-2-responsive cells in the FUBM are different from those of mature NK cells in that they are MAC-I+, NKl. I+, CD3-and susceptible to boosting by IFN-a. 0 1992 Academic press, hc. 3 Abbreviations used: IL-2, interleukin-2; NK, natural killer; 5-FU, 5-fluorouracil; IL-4, interleukin-4; IL-1, interleukin-1; BM, bone marrow; IL-2/r, interleukin-2 receptor: FUBM, bone marrow from 5-fluorouraciltreated mice; FCS, fetal calf serum. 323