T-bet-independent effects of IL-12 family cytokines on regulation of Th17 responses to infection (139.5)

Abstract

Abstract T-bet is an IFN-γ-inducible transcription factor that promotes Th1 differentiation. Previously we reported that T-bet (Tbx21)-deficient mice develop a robust Th17 response to parasitic infection, despite a normal Th1/IFN-γ response. The purpose of this study was to determine if IFN-γ exerted any influence on antigen-specific Th17 responses to T. cruzi, a parasite and causative agent of Chagas disease. Neutralization of endogenous IFN-γ or addition of recombinant IFN-γ to purified CD4+ T cell cultures from T. cruzi-infected mice had minimal effect on IL-17 production. CD4+ T cells expressed IFN-γRα, thus were capable of responding to IFN-γ. To determine if IFN-γ could act in an APC-dependent manner, we neutralized IFN-γ and IL-12 in splenocyte cultures, since one effect of IFN-γ on APC is induction of IL-12. While anti-IFN-γ modestly increased IL-17 production, addition of anti-IL-12 led to a significant enhancement of antigen-specific IL-17. In contrast, addition of IL-23 to T-bet-deficient cultures led to a striking increase in IL-17 production. These data show that IL-12 and IL-23 can influence Th17 responses in a T-bet-independent manner; and that the effects of IFN-γ are not necessarily related to its ability to induce T-bet expression in T cells. These data further illustrate the synergy between T cell and APC-intrinsic factors in regulation of Th17 responses to infection.