DNA methylation of TH1/TH2 cytokine genes affects sensitization and progress of experimental asthma

J Allergy Clin Immunol. 2012 Jun;129(6):1602-10.e6. doi: 10.1016/j.jaci.2011.12.963. Epub 2012 Jan 24.


Background: Epigenetic changes in DNA methylation have recently been demonstrated to be involved in effector T-cell polarization, resulting in differential secretion of T(H)1 and T(H)2 cytokines. However, the contribution to the development of a chronic inflammatory phenotype remains still unclear.

Objective: We sought to investigate changes in DNA methylation in marker genes of T-cell subsets during allergen sensitization/challenge and their influence on the development of an allergic airway inflammatory response.

Methods: The relationship between changes in DNA methylation and phenotype development were examined in a well-established model of experimental asthma. DNA methylation was investigated at genomic loci associated with T(H)1 (IFNG promoter) or T(H)2 (conserved noncoding sequence 1 [CNS1]) cytokine production by using bisulfite pyrosequencing.

Results: Analysis of CD4(+) T cells revealed a significant increase in DNA methylation at the IFNG promoter after allergen sensitization/challenge, which correlated with decreased IFN-γ cytokine expression, whereas only minor changes were observed at the CNS1 locus. Furthermore, the increase in DNA methylation at the IFNG promoter could be reversed with a DNA methyltransferase (DNMT) inhibitor in vitro and in vivo with beneficial effects on sensitization status and allergic phenotype. The specific importance of the DNA methylation status in CD4(+) T cells could be confirmed by using adoptive transfer experiments.

Conclusion: We here report the novel finding that epigenetic regulation in T cells contributes to the development of experimental asthma and can be targeted pharmacologically.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Asthma / genetics*
  • Asthma / immunology
  • Azacitidine / analogs & derivatives
  • Azacitidine / pharmacology
  • CD4-Positive T-Lymphocytes / drug effects
  • CD4-Positive T-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / metabolism
  • Cytokines / genetics*
  • DNA (Cytosine-5-)-Methyltransferases / antagonists & inhibitors
  • DNA Methylation* / drug effects
  • Decitabine
  • Epigenesis, Genetic
  • Female
  • Interferon-gamma / genetics
  • Mice
  • Mice, Inbred BALB C
  • Mice, SCID
  • Promoter Regions, Genetic
  • Th1 Cells / immunology*
  • Th1 Cells / metabolism
  • Th2 Cells / drug effects
  • Th2 Cells / immunology*
  • Th2 Cells / metabolism


  • Cytokines
  • Decitabine
  • Interferon-gamma
  • DNA (Cytosine-5-)-Methyltransferases
  • Azacitidine