The clinical implication and molecular mechanism of preferential IL-4 production by modified glycolipid-stimulated NKT cells
Shinji Oki, … , Takashi Yamamura, Sachiko Miyake
Shinji Oki, … , Takashi Yamamura, Sachiko Miyake
Published June 1, 2004
Citation Information: J Clin Invest. 2004;113(11):1631-1640. https://doi.org/10.1172/JCI20862.
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The clinical implication and molecular mechanism of preferential IL-4 production by modified glycolipid-stimulated NKT cells

Abstract

OCH, a sphingosine-truncated analog of α-galactosylceramide (αGC), 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-γ 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-γ 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 “αGC-loaded” CD1d molecules. Interestingly, transcription of IFN-γ but not that of IL-4 was sensitive to cycloheximide treatment, indicating the intrinsic involvement of de novo protein synthesis for IFN-γ production by NKT cells. Finally, we determined c-Rel was preferentially transcribed in αGC-stimulated but not in OCH-stimulated NKT cells and was essential for IFN-γ 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.

Authors

Shinji Oki, Asako Chiba, Takashi Yamamura, Sachiko Miyake

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Figure 4

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Differential sensitivity to CsA and CHX for transcriptional upregulation...
Differential sensitivity to CsA and CHX for transcriptional upregulation of IFN-γ, IL-4, and other cytokines. (A) Sorted NKT cells were pretreated with CsA (1 ∝g/ml) or with CHX (10 ∝g/ml) or without either reagent for 10 minutes and were then stimulated with immobilized mAb to CD3 for the indicated periods of time. Total RNA was extracted from each sample and analyzed for the relative amount of transcript of IFN-γ or IL-4. Data are presented as the amount of transcript in each sample relative to GAPDH. (B) Sorted NKT cells were pretreated with CsA (1 ∝g/ml) or with CHX (10 ∝g/ml) or without either reagent as shown in A. Total RNA was extracted from each sample and was analyzed for the relative amount of transcripts of IL-2, GM-CSF, or TNF-α. Data are presented as the relative amount of transcript in each sample.