The overall aim of this proposal is to understand the role of NF-kB in the regulation of the immune response to Toxoplasma gondii. T. gondii is an opportunistic pathogen in patients with acquired and primary deficiencies in cell mediated immunity. Resistance to this pathogen is based on the production of IL-12 which is required for NK and T cell production of IFN-g the major mediator of resistance to T. gondii. The NF-icB proteins are a family of transcription factors associated with many of the events that lead to the production of IFN-g required for resistance to T. gondii. For example, NF-icB is associated with the production of IL-12, and the ability of IL-12 to stimulate the production of IFN-'y is dependent on co-factors, such as IL-18 and CD28, which activate NF-kB. Thus, NF-kB is likely to be involved in resistance to T. gondii. Our studies have shown that infection with T. gondii leads to activation of NF-icB and that two members of this family, c-Rel and Rem, are required for optimal production of IFN-g. Additional studies using a transgenic mouse which expresses a specific inhibitor of NF-icB in 'I cells, indicates that the activation of NF-kB in I cells is required for the development of protective IFN-g responses. Based on these preliminary studies, we propose to perform studies which address the molecular and cellular basis for the role of NF-kB in the development of IFN-g responses. The proposed studies will not only provide a mechanism for why mice deficient in NF-kB mediated signaling are susceptible to toxoplasmosis, but will also provide novel insights into the mechanisms that lead to the production of IFN-g, a cytokine critical for resistance to many of the opportunistic infections which affect patients with AIDS.
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