Preferential Th2 polarization by OCH is supported by incompetent NKT cell induction of CD40L and following production of inflammatory cytokines by bystander cells in vivo

The altered glycolipid ligand OCH is a selective inducer of Th2 cytokines from NKT cells and a potent therapeutic reagent for Th1-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-c production. Here we demonstrate that OCH induces lower production of IFN-c, not only by NKT cells but also by NK cells compared with a-galactosylceramide. OCH induced lower IL-12 production due to ineffective primary IFN-c and CD40 ligand expression by NKT cells, and resulted in lower secondary IFN-c induction. Co-injection of a sub-optimal dose of IFN-c 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-c predominance. Furthermore, CpG oligodeoxynucleotide augmented IL-12 production when co-administrated with OCH, resulting in increased IFN-c production. Taken together, the lower IL-12 production and subsequent lack of secondary IFN-c burst support the effective Th2 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-c or IL-4 according to the availability of IL-12.