NF-kappaB and the regulation of innate and adaptive lymphocyte responses required for resistance to Toxoplasma gondii

The parasitic organism, Toxoplasma gondii, is a significant source of morbidity and mortality in humans. While the immune response to this infection is well characterized, there remain many questions about the signaling processes that lead to immune cell activation and effector functions required for resistance to this pathogen. Immunity to T. gondii consists of an innate response that leads to the activation of accessory cells and NK cells which provide a limited mechanism of resistance during the acute phase of infection. These events are followed by the development of adaptive immunity involving CD4+ and CD8+ T cells which are required for long-term control of this parasite. A common feature of these innate and adaptive components is the ability of NK and T cells to produce IFN-γ that is essential for resistance to T. gondii. Signaling pathways that lead to the activation of the Nuclear Factor-kappaB (NF-κB) family of transcription factors, provide the basis for many innate and adaptive immune responses, including the production of IFN-γ. The studies presented here reveal the importance of NF-κB in the expansion of an antigen-specific T cell population and in NK and T cell production of IFN-γ during infection. Interestingly, despite the use of similar receptors and signaling molecules by NK and T cells, there are fundamental differences in the structure of the IFN-γ gene that explain the different kinetics of IFN-γ production by these cells. Lastly, studies that have focused on the role of individual NF-κB family members have revealed distinct roles for c-Rel and p50 (NF-κB1) in the ability of NK cells to proliferate and produce IFN-γ. Together, these studies demonstrate the importance of the NF-κB system in resistance to T. gondii and have provided new insights into the basis for innate and adaptive production of IFN-γ