Repression of interleukin-4 in T helper type 1 cells by Runx/Cbf beta binding to the Il4 silencer.
Interferon gamma (IFN gamma) is the hallmark cytokine produced by T helper type 1 (Th1) cells, whereas interleukin (IL)-4 is the hallmark cytokine produced by Th2 cells. Although previous studies have revealed the roles of cytokine signaling and of transcription factors during differentiation of Th1 or Th2 cells, it is unclear how the exclusive expression pattern of each hallmark cytokine is established. The DNaseI hypersensitivity site IV within the mouse Il4 locus plays an important role in the repression of Il4 expression in Th1 cells, and it has been named the Il4 silencer. Using Cbf beta- or Runx3-deficient T cells, we show that loss of Runx complex function results in derepression of IL-4 in Th1 cells. Binding of Runx complexes to the Il4 silencer was detected in naive CD4(+) T cells and Th1 cells, but not in Th2 cells. Furthermore, enforced expression of GATA-3 in Th1 cells inhibited binding of Runx complexes to the Il4 silencer. Interestingly, T cell-specific inactivation of the Cbf beta gene in mice led to elevated serum immunoglobulin E and airway infiltration. These results demonstrate critical roles of Runx complexes in regulating immune responses, at least in part, through the repression of the Il4 gene.
Naoe
Yoshinori
Y
Institute of Physical and Chemical Research, Research Center for Allergy and Immunology, Turumi-ku, Yokohama, Kanagawa 230-0045, Japan.
Setoguchi
Ruka
R
Akiyama
Kaori
K
Muroi
Sawako
S
Kuroda
Masahiko
M
Hatam
Farah
F
Littman
Dan R
DR
Taniuchi
Ichiro
I
D000818:Animals; D001249:Asthma / Q000378:metabolism; D023081:CCAAT-Binding Factor / Q000378:metabolism*; D018106:CD28 Antigens / Q000096:biosynthesis; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D002454:Cell Differentiation; D050676:Core Binding Factor Alpha 2 Subunit / Q000378:metabolism*; D004742:Enhancer Elements, Genetic; D020868:Gene Silencing; D007107:Immune System; D015847:Interleukin-4 / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D011485:Protein Binding; D013601:T-Lymphocytes / Q000378:metabolism; D018417:Th1 Cells / Q000378:metabolism*
D023081:CCAAT-Binding Factor; D018106:CD28 Antigens; D050676:Core Binding Factor Alpha 2 Subunit; C493726:Runx1 protein, mouse; D015847:Interleukin-4