The broad purpose of this work is to further understand how microorganisms and vaccine adjuvants via their interaction with antigen presenting cells, such as macrophages and dendritic cells, affect the generation of T cell mediated immune responses via their ability to regulate the production of critical cytokines, such as IL-12 and IL-10. We have focused our work on the regulation of IL-12 production by G-protein signaling. Over the past year we have demonstrated that signaling via Gi2alpha coupled receptors can significantly alter immune responses to pathogens by altering the amount of IL-12 that is produced by antigen presenting cells. We have focused on 2 models of infection in mice and can show that signals via Gi2alpha are important for the inhibition or control of IL-12 production and cell-mediated immune responses to Leishmania major infection, while signals via this pathway are important for the positive induction of IL-12 in response to infection by another parasitic pathogen, Toxoplasma gondii. We are currently determining why the same signaling pathway can have such dramatically different effects on immune responses depending on the invading pathogen. We are also exploring ways to exploit these signaling pathways for suppression of autoimmune disease or the augmentation of immunity to pathogens. Finally, we are exploring the signaling pathways by which G-proteins regulate the production of IL-12 and other cytokines produced by macrophages and dendritic cells.
