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.
View: Text | PDF
Article Immunology Article has an altmetric score of 3

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

×

Figure 2

Options: View larger image (or click on image) Download as PowerPoint
Differential properties of structurally distinct glycolipid derivatives....
Differential properties of structurally distinct glycolipid derivatives. (A) Structures of αGC, OCH, and two other glycolipid ligands for NKT cells. F-2/S-3 has a truncation of two hydrocarbons in the fatty acyl chain (F) and of three hydrocarbons in the sphingosine chain (S) in comparison with αGC. OCH can be called F-2/S-9 accordingly. The numbers of truncated hydrocarbons in either lipid chain are shown along the left margin as negative integers. (B) Effect of αGC, OCH, and other glycolipids on proliferation and cytokine production of splenocytes. Splenocytes were stimulated with various concentrations (conc.) of αGC (filled circles), OCH (open circles), F-2/S-3 (filled triangles), or F-2/S-7 (open triangles) for 72 hours. Incorporation of [3H]thymidine (1 ∝Ci/well) during the final 16 hours of the culture was assessed (left), and IL-4 (center) or IFN-γ (right) in the supernatants was measured by ELISA. (C) Kinetic analysis of the loading of αGC (filled circles) or OCH (open circles) onto CD1d+ APCs. See Methods for details. One experiment representative of two independent experiments with similar results is shown. (D) Calcium influx into NKT hybridoma cells after coculture with CD1d+ APCs pulsed with αGC, OCH, F-2/S-3, or F-2/S-7. Data are presented as the activity remaining when the respective activity of glycolipid-loaded APCs for activation of the NKT cell hybridoma at time 0 was defined as 100%. Data are representative of three experiments with similar results.