The interleukin-4 enhancer CNS-2 is regulated by Notch signals and controls initial expression in NKT cells and memory-type CD4 T cells.
Epigenetic changes in chromatin structure at the T helper (Th2) locus correlate with interukin-4 (IL-4) and IL-13 expression during Th2 differentiation. By using a transgenic green fluorescence protein (GFP) reporter system, we show that conserved noncoding sequence-2 (CNS-2), located downstream of the Il4 locus, is a constitutively active enhancer in NKT cells as well as in a subset of CD44(hi) memory phenotype CD4+ T cells. CNS-2 enhancer activity and initial IL-4 expression in CD44(hi) CD4+ T cells were abolished in mice with a CD4-specific deletion of the transcriptional mediator of Notch signaling, Rbp-j. Depletion of CNS-2 active CD4+ T cells markedly decreased Th2 differentiation from naive CD4 T cells and antigen-specific IgE production after in vivo priming. These findings indicate that Notch-regulated CNS-2 enhancer controls initial IL-4 expression in NKT and memory phenotype CD4+ T cells and that CNS-2 active CD44(hi) memory phenotype T cells are important in facilitating Th2 differentiation of naive CD4+ T cells in allergic responses.
Tanaka
Shinya
S
Laboratory for Signal Network, Research Center for Allergy and Immunology, RIKEN Yokohama Institute, Suehiro-cho 1-7-22, Tsurumi, Yokohama, Kanagawa 230-0045, Japan; Research Institute for Biological Sciences, Tokyo University of Science, 2669 Yamazaki, Noda City, Chiba 278-0022, Japan.
Tsukada
Jun
J
Laboratory for Signal Network, Research Center for Allergy and Immunology, RIKEN Yokohama Institute, Suehiro-cho 1-7-22, Tsurumi, Yokohama, Kanagawa 230-0045, Japan; Research Institute for Biological Sciences, Tokyo University of Science, 2669 Yamazaki, Noda City, Chiba 278-0022, Japan.
Suzuki
Wataru
W
Research Institute for Biological Sciences, Tokyo University of Science, 2669 Yamazaki, Noda City, Chiba 278-0022, Japan.
Hayashi
Katsuhiko
K
The Henry Wellcome Building of Cancer and Developmental Biology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QN, United Kingdom.
Tanigaki
Kenji
K
Department of Medical Chemistry, Graduate School of Medicine, Kyoto University, Yoshida-Konoe, Sakyo-ku, Kyoto 606-8501, Japan.
Tsuji
Masayuki
M
Department of Medical Chemistry, Graduate School of Medicine, Kyoto University, Yoshida-Konoe, Sakyo-ku, Kyoto 606-8501, Japan.
Inoue
Hiromasa
H
Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
Honjo
Tasuku
T
Department of Medical Chemistry, Graduate School of Medicine, Kyoto University, Yoshida-Konoe, Sakyo-ku, Kyoto 606-8501, Japan.
Kubo
Masato
M
Laboratory for Signal Network, Research Center for Allergy and Immunology, RIKEN Yokohama Institute, Suehiro-cho 1-7-22, Tsurumi, Yokohama, Kanagawa 230-0045, Japan. Electronic address: raysolfc@rcai.riken.jp.
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D004742:Enhancer Elements, Genetic / Q000235:genetics*; D005786:Gene Expression Regulation; D018960:Hyaluronan Receptors / Q000032:analysis; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein / Q000235:genetics / Q000378:metabolism*; D007156:Immunologic Memory / Q000235:genetics; D015847:Interleukin-4 / Q000235:genetics*; D007694:Killer Cells, Natural / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D016176:T-Lymphocyte Subsets / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology*
D018960:Hyaluronan Receptors; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; D051880:Receptors, Notch; D015847:Interleukin-4