title: Epigenetic and transcriptional programs lead to default IFN-gamma production by gammadelta T cells.
abstract: 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.
authors.affiliation: Section of Rheumatology, Department of Medicine, Yale School of Medicine, New Haven, CT 06520, USA.
authors.forename: Liang
authors.initials: L
authors.lastname: Chen
authors.forename: Weifeng
authors.initials: W
authors.lastname: He
authors.forename: Sean T
authors.initials: ST
authors.lastname: Kim
authors.forename: Jian
authors.initials: J
authors.lastname: Tao
authors.forename: Yunfei
authors.initials: Y
authors.lastname: Gao
authors.forename: Hongbo
authors.initials: H
authors.lastname: Chi
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Intlekofer
authors.forename: Bohdan
authors.initials: B
authors.lastname: Harvey
authors.forename: Steven L
authors.initials: SL
authors.lastname: Reiner
authors.forename: Zhinan
authors.initials: Z
authors.lastname: Yin
authors.forename: Richard A
authors.initials: RA
authors.lastname: Flavell
authors.forename: Joe
authors.initials: J
authors.lastname: Craft
mesh_terms: D000818:Animals; D019175:DNA Methylation; D044127:Epigenesis, Genetic / Q000276:immunology*; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology*; D008213:Lymphocyte Activation; D051379:Mice; D018345:Mice, Knockout; D040641:Quantitative Trait Loci / Q000276:immunology; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000172:deficiency / Q000276:immunology*; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000276:immunology*; D020825:T-Box Domain Proteins / Q000096:biosynthesis / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D014158:Transcription, Genetic / Q000276:immunology*
chemical_list: C491198:Eomes protein, mouse; D016693:Receptors, Antigen, T-Cell, alpha-beta; D016692:Receptors, Antigen, T-Cell, gamma-delta; D020825:T-Box Domain Proteins; D007371:Interferon-gamma