title: Regulation of proinflammatory Th17 responses during Trypanosoma cruzi infection by IL-12 family cytokines.
abstract: 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.
authors.affiliation: Department of Microbiology and Immunology, Virginia Commonwealth University, Medical College of Virginia, Richmond, VA 23298, USA.
authors.forename: Dustin
authors.initials: D
authors.lastname: Cobb
authors.forename: Ronald B
authors.initials: RB
authors.lastname: Smeltz
mesh_terms: D000818:Animals; D014355:Chagas Disease / Q000276:immunology* / Q000469:parasitology / Q000473:pathology; D005786:Gene Expression Regulation; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology; D018664:Interleukin-12 / Q000235:genetics / Q000276:immunology*; D020381:Interleukin-17 / Q000235:genetics / Q000276:immunology; D007378:Interleukins / Q000235:genetics / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015398:Signal Transduction / Q000276:immunology; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000469:parasitology; D020825:T-Box Domain Proteins / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D058504:Th17 Cells / Q000166:cytology / Q000276:immunology* / Q000469:parasitology; D014349:Trypanosoma cruzi / Q000276:immunology*; D000098815:T-bet Transcription Factor
chemical_list: C486767:Il27 protein, mouse; D020381:Interleukin-17; D007378:Interleukins; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D018664:Interleukin-12; D007371:Interferon-gamma