IL-18 enhances IL-4 production by ligand-activated NKT lymphocytes: a pro-Th2 effect of IL-18 exerted through NKT cells.
NKT cells are a remarkably versatile population whose functional capacities are determined by cytokines present in their microenvironment. In this study, we provide evidence for a new immunoregulatory effect of the proinflammatory cytokine IL-18 on NKT cells. We found that IL-18, mainly known for its involvement in NK cell activation and in Th 1 immune responses, substantially enhanced IL-4 production as well as the percentage of IL-4(+) cells among NKT lymphocytes activated by their specific ligand alpha-galactosylceramide (alpha-GalCer). The effect of IL-18 on IL-4 production by activated NKT cells took place both in vivo and in vitro and was not affected by IL-12 which increased IFN-gamma secretion in the same conditions. We show that NKT cells are the main targets for IL-18-induced IL-4 production since it occurred neither in NKT-deficient mice nor after stimulation of Th2 lymphocytes. Finally, we provide evidence that the IL-4 promptly generated by NKT cells in response to IL-18 plus alpha-galactosylceramide in vivo can effectively contribute to the adaptive Th2 immune response by up-regulating the early activation marker CD69 on B cells. Our data support the notion that, in contrast to the exclusive IFN-gamma inducer IL-12, IL-18 acts in a more subtle manner as a costimulatory factor in both pro-Th1 and pro-Th2 responses depending on the nature of the stimulation and the target cells.
Leite-De-Moraes
M C
MC
Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8603, Université René Descartes, Paris V, Hôpital Necker, Paris, France. leite@infobiogen.fr
Hameg
A
A
Pacilio
M
M
Koezuka
Y
Y
Taniguchi
M
M
Van Kaer
L
L
Schneider
E
E
Dy
M
M
Herbelin
A
A
D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000502:physiology*; D000818:Animals; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology; D002469:Cell Separation; D005699:Galactosylceramides / Q000008:administration & dosage; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D007371:Interferon-gamma / Q000096:biosynthesis; D020382:Interleukin-18 / Q000008:administration & dosage / Q000502:physiology*; D015847:Interleukin-4 / Q000096:biosynthesis* / Q000502:physiology; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D008024:Ligands; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D013154:Spleen / Q000166:cytology; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology* / Q000378:metabolism; D013950:Thymus Gland / Q000166:cytology
D000276:Adjuvants, Immunologic; D005699:Galactosylceramides; D020382:Interleukin-18; D008024:Ligands; D015847:Interleukin-4; D007371:Interferon-gamma