T-bet Inhibits the In Vivo Differentiation of Parasite-Specific CD4+ Th17 Cells in a T Cell-Intrinsic Manner

Abstract

CD4+ Th17 cells have emerged as a new T cell subset in the Th1/Th2 paradigm, and efforts have shifted toward understanding the factors that regulate their development in vivo. To analyze the role of the transcription factor T-bet in regulation of Th17 cells, we used a murine model of Trypanosoma cruzi infection, a protozoan parasite that causes Chagas disease in humans. Infection of Tbx21−/− mice led to normal, unimpaired development of Ag-specific CD4+ T cells producing IFN-γ. However, a robust Th17 response developed concomitant with Th1 responses. Despite significant IFN-γ production, the physiological effects of Th17 responses prevailed as there was a sharp increase in Gr-1+Ly6G+ neutrophils. Adoptive transfer of T cells from infected Tbx21−/− mice into Rag-2−/− mice (Tbx21+/+) revealed that CD4+ T cells maintained their IL-17-producing phenotype, including those cells capable of producing both IFN-γ and IL-17. Furthermore, and in contrast to the effects of IL-2 on Th17 development, IL-2 had no effect on IL-17 production by primed T cells. Importantly, adoptive transfer of T cells from naive Tbx21−/− mice into infected Rag-2−/− mice recapitulated the differentiation of T. cruzi-specific Th17 cells observed in infected Tbx21−/− mice. Conversely, transfer of wild-type T cells into infected Tbx21−/− mice did not reveal an increase in Th17 development. These results demonstrate that T-bet regulates the differentiation of T. cruzi-specific Th17 cells in vivo in a T cell-intrinsic manner. These data provide important insight into the role of T-bet in regulation of parasite-specific Th17 responses.