Janus-kinase-3-dependent signals induce chromatin remodeling at the Ifng locus during T helper 1 cell differentiation.
Differentiation of naive CD4+ T cells into T helper type 1 (Th1) effector cells requires both T cell receptor (TCR) signaling and cytokines such as interleukin-12 and interferon gamma (IFN-gamma). Here, we report that a third cytokine signal, mediated by the Janus family tyrosine kinase 3 (Jak3) and signal transducer and activator of transcription 5 (STAT5) pathway, is also required for Th1 cell differentiation. In the absence of Jak3-dependent signals, naive CD4+ T cells proliferate robustly but produce little IFN-gamma after Th1 cell polarization in vitro. This defect is not due to reduced activation of STAT1 or STAT4 or to impaired upregulation of the transcription factor T-bet. Instead, we find that T-bet binding to the Ifng promoter is greatly diminished in the absence of Jak3-dependent signals, correlating with a decrease in Ifng promoter accessibility and histone acetylation. These data indicate that Jak3 regulates epigenetic modification and chromatin remodeling of the Ifng locus during Th1 cell differentiation.
Department of Pathology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
Min
M
Shi
Tsung H
TH
Lin
Kenneth C
KC
Appell
Leslie J
LJ
Berg
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D002454:Cell Differentiation; D042002:Chromatin Assembly and Disassembly; D016207:Cytokines / Q000276:immunology / Q000378:metabolism*; D044127:Epigenesis, Genetic; D007371:Interferon-gamma / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D053616:Janus Kinase 3 / Q000378:metabolism*; D051379:Mice; D008817:Mice, Mutant Strains; D011401:Promoter Regions, Genetic; D050791:STAT Transcription Factors / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D018417:Th1 Cells / Q000166:cytology* / Q000276:immunology / Q000378:metabolism*
D016207:Cytokines; D050791:STAT Transcription Factors; D050799:STAT5 Transcription Factor; D007371:Interferon-gamma; D053616:Janus Kinase 3