Paralysis of dendritic cell IL-12 production by microbial products prevents infection-induced immunopathology

Interleukin-12 plays a major role in immunity to intracellular pathogens by governing the development of IFN gamma-dependent host resistance. Neverthe less, unregulated IL-12 synthesis can lead to immunopathology, an outcome p revented by the concurrent expression of interleukin-10. Dendritic cells (D C) are an important source of the initial IL-12 stimulated by microbial age nts. Here, we show that, following systemic triggering, DC can no longer be restimulated to produce IL-12 in vivo while continuing to respond in vitro . When infected with Toxoplasma gondii during this refractory state, mice m ount impaired acute IFN gamma responses and, in the case of IL-10-deficient animals, are protected from cytokine-induced mortality. These findings dem onstrate a previously unrecognized form of immunologic paralysis involving DC that can protect from infection-induced immunopathology.