Cooperation of Natural Killer Cell Stimulatory Factor/Interleukin-12 with Other Stimuli in the Induction of Cytokines and Cytotoxic Cell-Associated Molecules in Human T and NK Cells

Abstract Natural killer cell deficiencies (NKDs) are an emerging phenotypic subtype of primary immune deficiency. NK cells provide a defense against virally infected cells using a variety of cytotoxic mechanisms, and patients who have defective NK cell development or function can present with atypical, recurrent, or severe herpesviral infections. The current pipeline for investigating NKDs involves the acquisition and clinical assessment of patients with a suspected NKD followed by subsequent in silico, in vitro, and in vivo laboratory research. Evaluation involves initially quantifying NK cells and measuring NK cell cytotoxicity and expression of certain NK cell receptors involved in NK cell development and function. Subsequent studies using genomic methods to identify the potential causative variant are conducted along with variant impact testing to make genotype-phenotype connections. Identification of novel genes contributing to the NKD phenotype can also be facilitated by applying the expanding knowledge of NK cell biology. In this review, we discuss how NKDs that affect NK cell cytotoxicity can be approached in the clinic and laboratory for the discovery of novel gene variants.

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Adrenergic β1- and β1+2-receptor blockade suppress the natural killer cell response to head-up tilt in humans

Journal of Applied Physiology ◽

10.1152/jappl.1997.83.5.1492 ◽

1997 ◽

Vol 83 (5) ◽

pp. 1492-1498 ◽

Cited By ~ 13

Author(s):

M. Klokker ◽

N. H. Secher ◽

P. Madsen ◽

M. Pedersen ◽

B. K. Pedersen

Keyword(s):

Natural Killer Cell ◽

Nk Cells ◽

Natural Killer ◽

Cell Response ◽

Nk Cell ◽

Killer Cell ◽

Saline Control ◽

Receptor Blockade ◽

Natural Killer Cell Response ◽

Head Up Tilt

Klokker, M., N. H. Secher, P. Madsen, M. Pedersen, and B. K. Pedersen. Adrenergic β1- and β1+2-receptor blockade suppress the natural killer cell response to head-up tilt in humans. J. Appl. Physiol. 83(5): 1492–1498, 1997.—To evaluate stress-induced changes in blood leukocytes with emphasis on the natural killer (NK) cells, eight male volunteers were followed during three trials of head-up tilt with adrenergic β1- (metoprolol) and β1+2- (propranolol) blockade and with saline (control) infusions. The β1- and β1+2-receptor blockade did not affect the appearance of presyncopal symptoms, but the head-up tilt induced a transient lymphocytosis that was abolished by β1+2-receptor blockade but not by β1-receptor blockade. Head-up tilt also resulted in delayed neutrophilia, which was insensitive to β-receptor blockade. Lymphocyte subset analysis revealed that the head-up tilt resulted in a twofold increase in the percentage and absolute number of CD3−/CD16+and CD3−/CD56+NK cells in peripheral blood and that this increase was partially blocked by metoprolol and abolished by propranolol. The NK cell activity on a per NK cell basis did not change during head-up tilt, indicating that the cytotoxic capability of NK cells recruited to circulation is unchanged. The data suggest that the head-up tilt-induced lymphocytosis was due mainly to CD16+and CD56+NK cells and that their recruitment to the blood was inhibited by β1- and especially β1+2-receptor blockade. Thus stress-induced recruitment of lymphocytes, and of NK cells in particular, is mediated by epinephrine through activation of β-receptors on the lymphocytes.

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Natural killer cells suppress human erythroid stem cell proliferation in vitro

Blood ◽

10.1182/blood.v63.2.260.260 ◽

1984 ◽

Vol 63 (2) ◽

pp. 260-269 ◽

Cited By ~ 66

Author(s):

KF Mangan ◽

ME Hartnett ◽

SA Matis ◽

A Winkelstein ◽

T Abo

Keyword(s):

Stem Cell ◽

Natural Killer Cell ◽

Nk Cells ◽

Natural Killer ◽

Nk Cell ◽

Killer Cell ◽

Human Natural Killer Cell ◽

Percoll Density Gradient Centrifugation

Abstract To determine the role of natural killer (NK) cells in the regulation of human erythropoiesis, we studied the effects of NK-enriched cell populations on the in vitro proliferation of erythroid stem cells at three different levels of maturation (day 14 blood BFU-E, day 5–6 marrow CFU-E, and day 10–12 marrow BFU-E). NK cells were enriched from blood by Percoll density gradient centrifugation and by fluorescence- activated cell sorting (FACS), using the human natural killer cell monoclonal antibody, HNK-1. The isolated enriched fractions were cocultured with autologous nonadherent marrow cells or blood null cells and erythropoietin in a methylcellulose erythroid culture system. Cells from low-density Percoll fractions (NK-enriched cells) were predominantly large granular lymphocytes with cytotoxic activity against K562 targets 6–10-fold greater than cells obtained from high- density Percoll fractions (NK-depleted cells). In coculture with marrow nonadherent cells (NA) at NK:NA ratios of 2:1, NK-enriched cells suppressed day 5–6 CFU-E to 62% (p less than 0.025) of controls, whereas NK-depleted cells slightly augmented CFU-E to 130% of controls (p greater than 0.05). In contrast, no suppression of day 10–12 marrow BFU-E was observed employing NK-enriched cells. The NK CFU-E suppressor effects were abolished by complement-mediated lysis of NK-enriched cells with the natural killer cell antibody, HNK-1. Highly purified HNK- 1+ cells separated by FACS suppressed marrow CFU-E to 34% (p less than 0.025) and marrow BFU-E to 41% (p less than 0.025) of controls. HNK- cells had no significant effect on either BFU-E or CFU-E growth. NK- enriched cells were poor stimulators of day 14 blood BFU-E in comparison to equal numbers of NK-depleted cells or T cells isolated by E-rosetting (p less than 0.01). Interferon boosting of NK-enriched cells abolished their suboptimal burst-promoting effects and augmented their CFU-E suppressor effects. These studies provide evidence for a potential regulatory role of NK cells in erythropoiesis. The NK suppressor effect is maximal at the level of the mature erythroid stem cell CFU-E. These findings may explain some hypoproliferative anemias that develop in certain NK cell-activated states.

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An activated murine B cell lymphoma line (A-20) produces a factor-like activity which is functionally related to human natural killer cell stimulatory factor

European Journal of Immunology ◽

10.1002/eji.1830221222 ◽

1992 ◽

Vol 22 (12) ◽

pp. 3173-3178 ◽

Cited By ~ 13

Author(s):

José Mengel ◽

Leopoldo Daré ◽

Gustavo Marcelo Daré ◽

Maristela Delgado ◽

Auro Nomizo ◽

...

Keyword(s):

Natural Killer Cell ◽

B Cell ◽

Natural Killer ◽

Cell Lymphoma ◽

Killer Cell ◽

B Cell Lymphoma ◽

Human Natural Killer Cell ◽

Lymphoma Line ◽

Stimulatory Factor

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Suppression of natural killer cell activity by adherent effusion cells of cancer patients. Suppression of motility, binding capacity and lethal hit of NK cells

British Journal of Cancer ◽

10.1038/bjc.1984.4 ◽

1984 ◽

Vol 49 (1) ◽

pp. 17-23 ◽

Cited By ~ 15

Author(s):

A Uchida ◽

M Colot ◽

M Micksche

Keyword(s):

Natural Killer Cell ◽

Nk Cells ◽

Natural Killer ◽

Cancer Patients ◽

Binding Capacity ◽

Natural Killer Cell Activity ◽

Killer Cell ◽

Cell Activity ◽

Killer Cell Activity

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Hemostatic Factors Contribute to Tumor Cell Metastatic Potential by a Mechanism Linked to Natural Killer Cell Function.

Blood ◽

10.1182/blood.v104.11.690.690 ◽

2004 ◽

Vol 104 (11) ◽

pp. 690-690 ◽

Cited By ~ 2

Author(s):

Joseph S. Palumbo ◽

Kathryn E. Talmage ◽

Jessica V. Massari ◽

Christine M. La Jeunesse ◽

Matthew J. Flick ◽

...

Keyword(s):

Natural Killer Cell ◽

Tumor Cell ◽

Nk Cells ◽

Natural Killer ◽

Platelet Activation ◽

Cell Function ◽

Nk Cell ◽

Killer Cell ◽

Metastatic Potential ◽

Natural Killer Cell Function

Abstract A linkage between hemostatic system components and tumor cell metastatic potential has been well established, but the underlying mechanism(s) by which various circulating and cell-associated coagulation factors and platelets promote tumor cell dissemination remains to be fully defined. One potential mechanism by which tumor cell-associated microthrombi might enhance metastatic potential is by interfering with the cytolytic elimination of tumor cell emboli by natural killer (NK) cells. In order to explore this hypothesis, we studied tumor dissemination in mice lacking either fibrinogen or Gαq, a G protein critical for platelet activation. Comparative studies of experimental lung metastasis in control and Gαq−/− mice showed that loss of platelet activation resulted in a two-orders-of-magnitude decrease in pulmonary metastatic foci formed by either Lewis lung carcinoma or B16 melanoma. The difference in metastatic success was not the result of differences in tumor growth rate, as tumors transplanted into the dorsal subcutis of Gαq−/− and wildtype animals grew at similar rates. Rather, tumor cell fate analyses using radiolabeled tumor cells showed that the survival of tumor cells within the lung was significantly improved in mice that retained platelet activation function relative to Gαq−/− mice with a profound platelet activation defect. In order to examine the potential interplay between platelet activation and natural killer cell function, we compared pulmonary tumor cell survival in cohorts of control and Gαq−/− mice immuno-depleted of NK cells with an anti-asialo GM1 antibody. Remarkably, platelet function was no longer a determinant of metastatic potential in mice lacking NK cells. Given that fibrin(ogen) is also an established determinant of metastatic success we explored whether the influence of this key hemostatic factor on tumor cell dissemination was also mechanistically-coupled to natural killer cell function. We interbred fibrinogen-deficient mice with Gz-Ly49A transgenic mice known to have a constitutive deficit in NK cells. In those cohorts of mice with normal NK cells, we affirmed the earlier finding that fibrinogen deficiency resulted in a significant diminution in metastatic potential. However, consistent with our findings in mice with defective platelet activation, fibrinogen was found to no longer be a determinant of metastatic potential in mice lacking NK cells. These data establish another important link between innate immune surveillance and the hemostatic system. Further, it appears that at least one mechanism by which tumor cell-associated microthrombi increase metastatic potential is by restricting NK cell-mediated tumor cell elimination. Given that NK cell cytotoxicity requires direct contact with any target cell, one attractive model presently being explored is that tumor cell-associated platelets physically block NK cell access to tumor cell emboli.

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