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Oki S, Tomi C, Yamamura T, Miyake S: Preferential T (h) 2 polarization by OCH is supported by incompetent NKT cell induction of CD40L and following production of inflammatory cytokines by bystander cells in vivo. Int Immunol. 2005 Dec;17(12):1619-29. Epub 2005 Nov 15.
The altered glycolipid ligand OCH is a selective inducer of T (h) 2 cytokines from NKT cells and a potent therapeutic reagent for T (h) 1-mediated autoimmune diseases. Although we have previously shown the intrinsic molecular mechanism of preferential IL-4 production by OCH-stimulated NKT cells, little is known about the extrinsic regulatory network for IFN-gamma production. Here we demonstrate that OCH induces lower production of IFN-gamma, not only by NKT cells but also by NK cells compared with alpha-galactosylceramide. OCH induced lower IL-12 production due to ineffective primary IFN-gamma and CD40 ligand expression by NKT cells, and resulted in lower secondary IFN-gamma induction. Co-injection of a sub-optimal dose of IFN-gamma and stimulatory anti-CD40 mAb compensates for the lower induction of IL-12 by OCH administration. IL-12 converts OCH-induced cytokine expression from IL-4 predominance to IFN-gamma predominance. Furthermore, CpG oligodeoxynucleotide augmented IL-12 production when co-administrated with OCH, resulting in increased IFN-gamma production. Taken together, the lower IL-12 production and subsequent lack of secondary IFN-gamma burst support the effective T (h) 2 polarization of T cells by OCH. In addition, highlighted in this study is the characteristic property of OCH that can induce the differential production of IFN-gamma or IL-4 according to the availability of IL-12. |
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