IL-23 acts in a novel fashion by antagonizing IL-12 induced IFN-γ secretion (95.16)

Abstract

Most studies have concluded that interleukin-23 (IL-23) plays a unique role in promoting IL-17 secreting T cells. While some reports have also characterized IL-23 as having redundant pro-inflammatory effects with IL-12, we have instead found that IL-23 can regulate the innate immune response in a novel manner, by antagonizing IL-12 induced secretion of interferon-γ (IFN-γ). Our recent data documents the rapid, innate production of IFN-γ from memory CD8 T cells, as well as NK cells, stimulated with IL-12 and IL-18. When splenocytes are cultured with IL-23, IFN-γ secretion in response to IL-12 is dramatically reduced, as measured by ELISA and intracellular cytokine staining. The impact of IL-23 is most prominent in CD8 T cells, but can also be seen in NK, NK-T, and CD4 T cells. We also show that IL-23 can regulate the induction of IFN-γ by endogenously produced IL-12 from Listeria monocytogenes infected macrophages. Furthermore, IL-23 appears to act directly on purified CD8 T cells to negatively regulate IFN-γ induced by IL-12. We are currently investigating the mechanism by which IL-23 inhibits IFN-γ secretion. In addition, experiments to determine if IL-23 can inhibit other effector functions are ongoing. Our data suggest that IL-23 may be a key player in determining the responsiveness of lymphocytes to IL-12 and their subsequent secretion of IFN-γ. This research is supported by NIH AI064592.