Epigenetic and transcriptional programs lead to default IFN-γ production by γδ T cells

gamma delta T cells have unique features and functions compared with alpha beta T cells and have been proposed to bridge the innate and adaptive immune responses. Our earlier studies detrionstrated that splenic gamma delta 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 gamma delta T cells. We show that the kinetics of IFN-gamma transcription is faster in gamma delta T cells compared with CD4(+) and CD8(+) T cells and that gamma delta 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 gamma delta T cells is hypomethylated relative to the same element in naive CD4(+) and CD8(+) T cells. Furthermore, naive gamma delta 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 gamma delta 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 gamma delta T cells in a T-bet-independent manner. Our results demonstrate that both epigenetic and transcriptional programs contribute to the early vigorous IFN-gamma delta production by gamma delta T cells.