Byung Hee Koha,1, Soo Seok Hwanga,1, Joo Young Kimb,c, Wonyong Leea, Min-Jong Kangd, Chun Geun Leed, Jung-Won Parkb,c, Richard A. Flavelle,f,2,3, and Gap Ryol Leea,e,2,3
aDepartment of Life Science, Sogang University, Seoul 121-742, Korea;
bDepartment of Internal Medicine,
cInstitute of Allergy, Yonsei University College of Medicine, Seoul 120-752, Korea; and
dSection of Pulmonary and Critical Care Medicine,
eDepartment of Immunobiology, and
fHoward Hughes Medical Institute, Yale School of Medicine, New Haven, CT 06520
Contributed by Richard A. Flavell, April 26, 2010 (sent for review February 5, 2010)
1B.H.K. and S.S.H. contributed equally to this work.
2R.A.F. and G.R.L. contributed equally to this work.
Previous studies have shown that Th2 cytokine genes on mouse chromosome 11 are coordinately regulated by the Th2 locus control region (LCR). To examine the in vivo function of Th2 LCR, we generated CD4-specific Th2 LCR-deficient (cLCR KO) mice using Cre-LoxP recombination. The number of CD4 T cells in the cLCR KO mouse was comparable to that in wild-type mice. The expression of Th2 cytokines was dramatically reduced in in vitro-stimulated naive CD4 T cells. Deletion of the LCR led to a loss of general histone H3 acetylation and histone H3-K4 methylation, and demethylation of DNA in the Th2 cytokine locus. Upon ovalbumin challenge in the mouse model of allergic asthma, cLCR KO mice exhibited marked reduction in the recruitment of eosinophils and lymphocytes in the bronchoalveolar lavage fluid, serum IgE level, lung airway inflammation, mucus production in the airway walls, and airway hyperresponsiveness. These results directly demonstrate that the Th2 LCR is critically important in the regulation of Th2 cytokine genes, in chromatin remodeling of the Th2 cytokine locus, and in the pathogenesis of allergic asthma.
chromatin remodeling, differentiation, locus control region
3To whom correspondence may be addressed.
Author contributions: R.A.F. and G.R.L. designed research; B.H.K., S.S.H., J.Y.K., W.L., M.-J.K., C.G.L., J.-W.P., and G.R.L. performed research; R.A.F. and G.R.L. analyzed data; and R.A.F. and G.R.L. wrote the paper.
The authors declare no conflict of interest.
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