A critical role for IL-18 in the proliferation and activation of NK1.1+ CD3- cells.
Like IL-12, IFN-gamma-inducing factor/IL-18 has been shown to stimulate T cells for IFN-gamma production and growth promotion. Considering the NK-stimulatory capacity of IL-12, we investigated the effect of IL-18 on NK lineage cells. A CD4- CD8- surface Ig- Ia- fraction of freshly prepared C57BL/6 spleen cells proliferated strikingly in response to combinations of IL-12 + IL-18 or IL-2 + IL-18, but not to the individual cytokines or IL-2 + IL-12. Cells proliferating in response to IL-2 + IL-18 were NK1.1+ CD3-, whereas IL-12 + IL-18-responsive cells were NK1.1- CD3-. Restimulation of the former cells with IL-12 + IL-18 or the latter cells with IL-2 + IL-18 resulted in the generation of NK1.1- CD3- or NK1.1+ CD3- cells, respectively. Moreover, a NK1.1+ CD3- CD4- CD8- surface Ig- Ia- population isolated from spleen cells was found to form NK1.1+ CD3- or NK1.1- CD3- blasts by stimulation with IL-2 + IL-18 or IL-12 + IL-18, respectively, and the NK1.1 positivity on these blasts was again reversed after restimulation with an alternative combined stimulus. Both types of blasts produced enormously large amounts of IFN-gamma in response to IL-12 + IL-18 and exhibited strikingly high levels of NK activity. These results indicate that IL-18 plays an obligatory role in inducing proliferation and activation of NK1.1+ CD3- CD4- CD8- cells and that the expression of the NK1.1 marker is reversible, depending on the cytokine used for stimulation in combination with IL-18.
Tomura
M
M
Biomedical Research Center, Osaka University Medical School, Suita, Japan.
Zhou
X Y
XY
Maruo
S
S
Ahn
H J
HJ
Hamaoka
T
T
Okamura
H
H
Nakanishi
K
K
Tanimoto
T
T
Kurimoto
M
M
Fujiwara
H
H
D000818:Animals; D000941:Antigens / Q000032:analysis*; D000950:Antigens, Ly; D000954:Antigens, Surface; D017252:CD3 Complex / Q000032:analysis*; D002478:Cells, Cultured; D016207:Cytokines / Q000494:pharmacology*; D007371:Interferon-gamma / Q000096:biosynthesis; D018664:Interleukin-12 / Q000494:pharmacology; D020382:Interleukin-18; D007376:Interleukin-2 / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000276:immunology*; D037181:Lectins, C-Type; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D055651:NK Cell Lectin-Like Receptor Subfamily B; D011506:Proteins / Q000032:analysis*
D000941:Antigens; D000950:Antigens, Ly; D000954:Antigens, Surface; D017252:CD3 Complex; D016207:Cytokines; D020382:Interleukin-18; D007376:Interleukin-2; C527211:Klrb1c protein, mouse; D037181:Lectins, C-Type; D055651:NK Cell Lectin-Like Receptor Subfamily B; D011506:Proteins; D018664:Interleukin-12; D007371:Interferon-gamma