A distinct IL-18-induced pathway to fully activate NK T lymphocytes independently from TCR engagement.
NK T lymphocytes are characterized by their ability to promptly generate IL-4 and IFN-gamma upon TCR engagement. Here, we demonstrate that these cells can also be fully activated in the absence of TCR cross-linking in response to the proinflammatory cytokine IL-18 associated with IL-12. NK T cells stimulated with IL-18 plus IL-12 proliferated, killed Fas+ target cells, and produced high levels of IFN-gamma without IL-4. In these conditions, IFN-gamma production was at least 10-fold higher than that upon TCR cross-linking. Interestingly, a 2-h pretreatment with IL-12 plus IL-18 sufficed to maintain the high IFN-gamma-producing potential during subsequent stimulation with anti-TCR mAbs or with the specific Ag alpha-galactosylceramide. Similar effects were observed in vivo, because splenic CD4+ NK T cells from MHC class II-deficient mice secreted IFN-gamma without further stimulation when removed 2 h after a single injection of IL-12 plus IL-18. In conclusion, our evidence for activation of NK T lymphocytes in response to IL-18 plus IL-12 in the absence of TCR engagement together with the maintenance of preferential IFN-gamma vs IL-4 production upon subsequent exposure to specific Ags is consistent with the active participation of this cell population in innate as well as acquired cellular immune responses.
Leite-De-Moraes
M C
MC
Centre National de la Recherche Scientifique, UMR 8603, Université René Descartes, Paris V, and Institut National de la Santé et de la Recherche, Unité 25, Hôpital Necker, Paris, France. leite@infobiogen.fr
Hameg
A
A
Arnould
A
A
Machavoine
F
F
Koezuka
Y
Y
Schneider
E
E
Herbelin
A
A
Dy
M
M
D000818:Animals; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic; D004347:Drug Interactions; D005802:Genes, MHC Class II; D007371:Interferon-gamma / Q000096:biosynthesis; D018664:Interleukin-12 / Q000494:pharmacology; D020382:Interleukin-18 / Q000494:pharmacology*; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology*; D008213:Lymphocyte Activation; D051379:Mice; D008817:Mice, Mutant Strains; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D013154:Spleen / Q000166:cytology / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D019014:fas Receptor / Q000276:immunology
D020382:Interleukin-18; D011948:Receptors, Antigen, T-Cell; D019014:fas Receptor; D018664:Interleukin-12; D007371:Interferon-gamma