Epigenetic and Transcriptional Programs Lead to Default IFN-γ Production by γδ T Cells

Gammadelta T cells have unique features and functions compared with alphabeta T cells and have been proposed to bridge the innate and adaptive immune responses. Our earlier studies demonstrated that splenic gammadelta T cells predominantly produce IFN-gamma upon activation in vitro, which is partially due to the expression of the Th1-specific transcription factor T-bet. In this study we have explored the epigenetic and transcriptional programs that underlie default IFN-gamma production by gammadelta T cells. We show that the kinetics of IFN-gamma transcription is faster in gammadelta T cells compared with CD4(+) and CD8(+) T cells and that gammadelta T cells produce significantly greater amounts of IFN-gamma in a proliferation-independent manner when compared with other T cell subsets. By analyzing the methylation pattern of intron 1 of the ifn-gamma locus, we demonstrate that this region in naive gammadelta T cells is hypomethylated relative to the same element in naive CD4(+) and CD8(+) T cells. Furthermore, naive gammadelta T cells constitutively express eomesodermin (Eomes), a transcription factor important for IFN-gamma production in CD8(+) T cells, and Eomes expression levels are enhanced upon activation. Retroviral transduction of activated gammadelta T cells from both wild-type and T-bet-deficient mice with a dominant negative form of Eomes significantly reduced IFN-gamma production, indicating a critical role for this transcription factor in mediating IFN-gamma production by gammadelta T cells in a T-bet-independent manner. Our results demonstrate that both epigenetic and transcriptional programs contribute to the early vigorous IFN-gamma production by gammadelta T cells.