Requirement for IFN-γ in IL-12 production induced by collaboration between Vα14+ NKT cells and antigen-presenting cells

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Abstract
Two cytokines IL-4 and IL-12 are known to determine the balance between Th1 and Th2 development. In addition to IL-4 production of Vα14+ NKT cells, they have recently been demonstrated to have the capacity to stimulate IL-12 production by antigen-presenting cells (APC). This study demonstrates that IFN-γ is absolutely required for the NKT cell-stimulated IL-12 production. Culture of B cell-depleted spleen cells from C57BL/6 mice with α-galactosylceramide (α-GalCer) capable of selectively stimulating Vα14/Jα281+ NKT cells resulted in the production of IL-12 together with IL-4. Whereas IL-4 production occurred in culture of IFN-γ–/– C57BL/6 splenocytes, the same culture failed to generate IL-12 production. While IL-12 production induced during culture of Vα14+ NKT cells and APC depended on the interaction between CD40 ligand on NKT cells and CD40 on APC, the expression levels of these key molecules were comparable in cells from wild-type and IFN-γ–/– mice. Addition of rIFN-γ to α-GalCer stimulated IFN-γ–/– splenocyte culture, and administration of rIFN-γ to α-GalCer-injected IFN-γ–/– mice resulted in the restoration of IL-12 production in vitro and in vivo. These results illustrate a mandatory role for IFN-γ in Vα14+ NKT cell-stimulated IL-12 production by APC.