Regulation of Proinflammatory Th17 Responses during Trypanosoma cruzi Infection by IL-12 Family Cytokines

Previously, we reported that the transcription factor T-bet (Tbx21) regulates Th17 responses to Trypanosoma cruzi infection in an IFN-γ-independent manner. In an effort to further understand this regulation, we examined the development and plasticity of Th17 cells during T. cruzi infection. Th17 cells recovered from infected Tbx21(-/-) mice were amenable to the inhibitory effects of T-bet, as ectopic expression of T-bet reduced IL-17 expression. We subsequently addressed the role of IL-12 family cytokines IL-12 and IL-27 and report that IL-12p35(-/-) mice infected with T. cruzi exhibited a significant increase in Th17 cells and Th17-associated inflammation. Ex vivo culture of these cells with IL-12 led to a dramatic reduction in IL-17 production and concomitant increase in IFN-γ. Importantly, the ability of IL-12 to suppress IL-17 was independent of IFN-γ. Surprisingly, and contrary to results reported for other pathogens, IL-27 had no inhibitory effect on Th17 development, as Ebi-3(-/-) mice failed to show any increase in their T. cruzi-specific Th17 response. Furthermore, IL-27 could not compensate or synergize with IL-12 to suppress IL-17 production ex vivo. Thus, we have established that IL-12, not IL-27, is critical for regulating Th17 responses to T. cruzi.