T-bet-independent effects of IL-12 family cytokines on regulation of Th17 responses to experimental T. cruzi infection

Tbx21 (i.e., T-bet) is an IFN-gamma-inducible transcription factor that promotes Th1 differentiation. Previously, we reported that Tbx21(-/-) mice develop a robust Th17 response to the parasite Trypanosoma cruzi, including CD4(+) T cell subsets producing IL-17 and IFN-gamma. Because of the known inhibitory effects of IFN-gamma on Th17 cells, the purpose of this study was to determine the contribution of IFN-gamma to regulation of Th17 differentiation during the course of T. cruzi infection. We observed that infection of IFN-gamma(-/-) or Stat-1(-/-) mice generated increased numbers of IL-17-producing cells. In sharp contrast to infected Stat-1(-/-) or Tbx21(-/-) mice, however, IFN-gamma(-/-) mice developed a lower overall Th17 response, suggesting that IFN-gamma was not required for T-bet-dependent activity, including T-bet-dependent expression of CXCR3. To determine if IFN-gamma could influence Th17 responses indirectly by acting on APCs, we neutralized IFN-gamma in cultures containing APC and T. cruzi antigens. Although anti-IFN-gamma increased IL-17 production modestly, anti-IFN-gamma and anti-IL-12 led to a significant enhancement of T. cruzi-specific IL-17 (P<0.01). In contrast to the inhibitory effects of IL-12, IL-23 was able to stimulate Tbx21(-/-) T cells and cause a striking increase in T. cruzi-specific IL-17. These data show that the IL-12 family of cytokines can influence Th17 responses in a T-bet-independent manner and that the effects of IFN-gamma are not necessarily related to its ability to induce T-bet expression in T cells. J. Leukoc. Biol. 88: 965-971; 2010.