Immune Regulation in Toxoplasmosis and Other Opportunistic Infections

Dendritic cell production of IL 12 is thought to be a major inititiation step in host resistance to Toxoplasma gondii. This year we demonstrated that interactions with the CC chemokine receptor CCR5 play an important role in both the parasite antigen induced mobilization of these cells into T cell areas of the spleen as well as in their production of IL 12. This CCR5 dependent IL 12 response was shown to be dependent on a G protein coupled signaling pathway triggered by the receptor in CD8 alpha positive DC. CCR5 deficient mice were shown to mount defective IL 12 responses and to be more susceptible to infection with T. gondii confiming the importance of the pathway in host resistance.
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Together these findings support the concept that the early induction of chemokines by invading pathogens is a critical step not only for the recruitment of DC but also for the determination of their subsequent immunologic function. While host resistance to T.gondii is clearly dependent on IL 12 induced IFN gamma , the mechanism by which IFN gamma activation mediates control of intracellular infection in both professional phagocytes and non hemapoietic cells is not clear.
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This year, we identified an IFN gamma inducible gene, IGTP (IFN inducible GTPase) which plays a critical role in host resistance to T. gondii by effecting intracellular control of infection in both compartments. Interestingly, while severely effecting resistance to T. gondii, IGTP deficiency has no effect on IFN dependent resistance to other infectious agents suggesting that members of this 47 kD family of GTP binding proteins may play pathogen specific roles in host immunity.