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.
Shi
Min
M
Department of Pathology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
Lin
Tsung H
TH
Appell
Kenneth C
KC
Berg
Leslie J
LJ
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