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.
Most studies have concluded that interleukin‐23 (IL‐23) promotes 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 (LM) infected macrophages. In vivo, LM infection induces higher serum IFN‐γ levels and a greater percentage of IFN‐γ + CD8 T cells in IL‐23p19 deficient mice as compared to wild‐type mice. We are currently investigating the mechanism by which IL‐23 inhibits IFN‐γ secretion, and if IL‐23 can inhibit other effector functions. 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.
Listeria monocytogenes (LM) is a gram-positive, intracellular bacterium that is commonly used to investigate the immune response to infection. Pro-inflammatory cytokines, such as IL-12 and IL-18, are secreted during LM infection to promote clearance of the bacteria through the induction of IFN-γ. LM secretes listeriolysin O (LLO) which allows the bacterium to invade the cytoplasm. Neither heat-killed LM (HKLM) nor LLO deficient LM (LLO−LM) actively produce LLO. When bone marrow derived macrophages (macs) and dendritic cells (DCs) are infected with LM, HKLM, or LLO−LM and co-cultured with naïve splenocytes, only macs or DCs infected with LM are able to induce IFN-γ secretion. ELISA data demonstrates that IL-12 is secreted from LM, HKLM, or LLO−LM infected macs and DCs, but IL-18 is only secreted from macs and DCs infected with LM. Therefore, IL-12 can be secreted by macs and DCs regardless of cytoplasmic invasion of LM whereas the secretion of IL-18 requires LM to gain access to the cytoplasm. When mice are infected with HKLM, there is no detectable IFN-γ secretion and this can be attributed to a lack of both IL-12 and IL-18. This implies that IL-12 is induced differently in response to HKLM in vivo versus in vitro. Further studies are ongoing to determine which pattern recognition receptors and cell types are responsible for recognizing and secreting IL-12 and IL-18 during in vivo LM infection.
Supported by NIH AI064592.
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