Epigenetic and transcriptional programs lead to default IFN-gamma production by gammadelta 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.
Chen
Liang
L
Section of Rheumatology, Department of Medicine, Yale School of Medicine, New Haven, CT 06520, USA.
He
Weifeng
W
Kim
Sean T
ST
Tao
Jian
J
Gao
Yunfei
Y
Chi
Hongbo
H
Intlekofer
Andrew M
AM
Harvey
Bohdan
B
Reiner
Steven L
SL
Yin
Zhinan
Z
Flavell
Richard A
RA
Craft
Joe
J
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*
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