The clinical implication and molecular mechanism of preferential IL-4 production by modified glycolipid-stimulated NKT cells.
OCH, a sphingosine-truncated analog of alpha-galactosylceramide (alphaGC), is a potential therapeutic reagent for a variety of Th1-mediated autoimmune diseases through its selective induction of Th2 cytokines from natural killer T (NKT) cells. We demonstrate here that the NKT cell production of IFN-gamma is more susceptible to the sphingosine length of glycolipid ligand than that of IL-4 and that the length of the sphingosine chain determines the duration of NKT cell stimulation by CD1d-associated glycolipids. Furthermore, IFN-gamma production by NKT cells requires longer T cell receptor stimulation than is required for IL-4 production by NKT cells stimulated either with immobilized mAb to CD3 or with immobilized "alphaGC-loaded" CD1d molecules. Interestingly, transcription of IFN-gamma but not that of IL-4 was sensitive to cycloheximide treatment, indicating the intrinsic involvement of de novo protein synthesis for IFN-gamma production by NKT cells. Finally, we determined c-Rel was preferentially transcribed in alphaGC-stimulated but not in OCH-stimulated NKT cells and was essential for IFN-gamma production by activated NKT cells. Given the dominant immune regulation by the remarkable cytokine production of ligand-stimulated NKT cells in vivo, in comparison with that of (antigen-specific) T cells or NK cells, the current study confirms OCH as a likely therapeutic reagent for use against Th1-mediated autoimmune diseases and provides a novel clue for the design of drugs targeting NKT cells.
Oki
Shinji
S
Department of Immunology, National Institute of Neuroscience, National Center for Neuroscience and Psychiatry, Tokyo, Japan.
Chiba
Asako
A
Yamamura
Takashi
T
Miyake
Sachiko
S
D000818:Animals; D006017:Glycolipids / Q000378:metabolism*; D007371:Interferon-gamma / Q000096:biosynthesis; D015847:Interleukin-4 / Q000096:biosynthesis*; D007694:Killer Cells, Natural / Q000378:metabolism*; D007700:Kinetics; D051379:Mice; D020569:Proto-Oncogene Proteins c-rel / Q000378:metabolism; D013601:T-Lymphocytes / Q000378:metabolism*
D006017:Glycolipids; D020569:Proto-Oncogene Proteins c-rel; D015847:Interleukin-4; D007371:Interferon-gamma