Enhancement of the synthetic ligand-mediated function of liver NK1.1Ag+ T cells in mice by interleukin-12 pretreatment.
We previously reported that mouse NK1.1 Ag+ T (NKT) cells activated by interleukin-12 (IL-12) act as anti-tumour/anti-metastatic effectors. However, IL-12 reportedly induces a rapid disappearance of liver NKT cells by activation-induced apoptosis. In the present study, however, we show that injection of IL-12 into mice merely down-regulates the NK1.1 expression of liver NKT cells and Vbeta8+ intermediate T-cell receptor cells and CD1d/alpha-galactosylceramide (alpha-GalCer)-tetramer reactive cells in the liver remained and did not decrease. Furthermore, when IL-12-pretreated (24 hr before) mice were injected with alpha-GalCer, not only serum interferon-gamma but also serum IL-4 concentrations increased several-fold in comparison to the control alpha-GalCer-injected mice. However, IL-12 pretreatment markedly up-regulated serum ALT levels and Fas-ligand expression on NKT cells after alpha-GalCer injection in middle-aged mice only. Consistently, the liver mononuclear cells (MNC) from IL-12-pretreated mice stimulated with alpha-GalCer in vitro produced much greater amounts of interferon-gamma and IL-4, and also showed a more potent cytotoxicity against tumour targets than those from mice pretreated with phosphate-buffered saline. Liver MNC from middle-aged mice, but not from young mice pretreated with IL-12, also showed increased cytotoxicity following in vitro alpha-GalCer stimulation against cultured hepatocytes. Furthermore, IL-12 treatment of middle-aged mice enhanced tumour necrosis factor receptor 1 mRNA expression in liver Vbeta8+ T cells, and in vitro experiments also revealed that IL-12 pretreatment of liver MNC from middle-aged mice enhanced their tumour necrosis factor-alpha production after alpha-GalCer stimulation. Synthetic ligand-mediated functions of NKT cells, including IL-4 production, are thus enhanced by IL-12 pretreatment.
Habu
Yoshiko
Y
Department of Microbiology, National Defence Medical College, Tokorozawa, Saitama, Japan.
Uchida
Takefumi
T
Inui
Takuo
T
Nakashima
Hiroyuki
H
Fukasawa
Masashi
M
Seki
Shuhji
S
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D000941:Antigens / Q000032:analysis*; D000950:Antigens, Ly; D000954:Antigens, Surface; D002478:Cells, Cultured; D003470:Culture Media; D016207:Cytokines / Q000097:blood; D003602:Cytotoxicity, Immunologic; D053222:Fas Ligand Protein; D005699:Galactosylceramides / Q000276:immunology; D015870:Gene Expression; D022781:Hepatocytes / Q000276:immunology; D018664:Interleukin-12 / Q000276:immunology*; D007694:Killer Cells, Natural / Q000276:immunology*; D037181:Lectins, C-Type; D008024:Ligands; D008099:Liver / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D055651:NK Cell Lectin-Like Receptor Subfamily B; D011506:Proteins / Q000032:analysis*; D012333:RNA, Messenger / Q000235:genetics; D018123:Receptors, Interleukin / Q000096:biosynthesis / Q000235:genetics; D053707:Receptors, Interleukin-12; D018124:Receptors, Tumor Necrosis Factor / Q000096:biosynthesis / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000941:Antigens; D000950:Antigens, Ly; D000954:Antigens, Surface; D003470:Culture Media; D016207:Cytokines; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D005699:Galactosylceramides; C527211:Klrb1c protein, mouse; D037181:Lectins, C-Type; D008024:Ligands; D008562:Membrane Glycoproteins; D055651:NK Cell Lectin-Like Receptor Subfamily B; D011506:Proteins; D012333:RNA, Messenger; D018123:Receptors, Interleukin; D053707:Receptors, Interleukin-12; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D000410:Alanine Transaminase; C103873:KRN 7000