Journal
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
Volume 129, Issue 6, Pages 1602-+Publisher
MOSBY-ELSEVIER
DOI: 10.1016/j.jaci.2011.12.963
Keywords
Epigenetics; T cells; experimental asthma
Categories
Funding
- Deutsche Forschungsgemeinschaft [SFB/TR22]
- LOEWE Excellence Centre UGMLC (Universities of Giessen & Marburg Lung Centre)
- Stiftung P.E. Kempkes, Marburg [10/07]
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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-gamma 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. (J Allergy Clin Immunol 2012; 129: 1602-10.)
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