Abstract
Natural killer (NK) cells play an important role in host defense mechanisms against infection and neoplasia. Interferon-α (IFN-α) has been shown to activate NK cells and to augment their cytotoxic activity, albeit its role in the maturation pathway of NK cells has not been elucidated. The present study examined whether IFN-α activates the immature NK subset (Free cells) to become cytotoxic and also ascertained whether IFN-α uses the same pathway of activation as that mediated by interleukin-2 (IL-2). Incubation of sorted Free cells overnight with IFN-α resulted in augmentation of their cytotoxic function against NK sensitive target cells. The enhanced cytotoxic activity was not accompanied by a new recruitment of NK-target binder cells but by an increase in the frequency of killer cells in the conjugate fraction. Activation of the Free subset by IFN-α resulted in upregulation of CD69, CD11b, and CD2 surface expression and stimulated secretion of IFN-γ. Unlike IL-2, IFN-α did not stimulate the Free cells to proliferate or secrete TNF-α and activation of cytotoxicity and modulation of surface antigens by IFN-α were independent of TNF-α. The failure of IFN-α to stimulate secretion and proliferation by Free cells appeared to be mediated by negative signals. This was corroborated in experiments demonstrating that when Free cells were cultured with both IFN-α and IL-2, a significant inhibition was observed for both the IL-2 dependent secretion of TNF-α and proliferation. These results demonstrate that IFN-α serves as both an activator and a regulator of NK function. Further, activation of the immature Free NK cells by IL-2 and IFN-α proceeds by TNF-α-dependent and independent pathways, respectively. The findings also support our contention that the mechanism of activation of the cytotoxic machinery of NK cells is not linked to the mechanism of activation of cytokine secretion and/or proliferation.
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Abbreviations
- IFN:
-
interferon
- IL:
-
interleukin
- PBL:
-
peripheral blood leukocytes
- PE:
-
phycoerythrin
- PE-GAM:
-
PE-conjugated Fab′2 goat anti-mouse IgG
- NK:
-
natural killer
- NRS:
-
normal rabbit serum
- TNF:
-
tumor necrosis factor
- FCS:
-
fetal calf serum
- FITC:
-
fluorescein isothiocyanate
- PBS:
-
phosphate-buffered saline
- MACS:
-
magnetic cell sorting
- ELISA:
-
enzyme-linked immunosorbent assay
- BSA:
-
bovine serum albumin
- PKC:
-
protein kinase C
- mAb:
-
monoclonal antibody
- PBMC:
-
peripheral blood mononuclear cells
- BCLL:
-
B-chronic lymphocytic leukemia
- E:
-
effector
- T:
-
target
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Jewett, A., Bonavida, B. Interferon-α activates cytotoxic function but inhibits interleukin-2-mediated proliferation and tumor necrosis factor-α secretion by immature human natural killer cells. J Clin Immunol 15, 35–44 (1995). https://doi.org/10.1007/BF01489488
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DOI: https://doi.org/10.1007/BF01489488