DNA methylation of Tb>Hb>1/Tb>Hb>2 cytokine genes affects sensitization and progress of experimental asthma

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• 作者：Stephanie Brand ; PhD^a ; ^&lowast ; ; D&ouml ; rthe Andrea Kesper ; PhD^a ; ^&lowast ; ; René ; Teich ; PhD^b ; ^&lowast ; ; Esma Kilic-Niebergall ; MSc^a ; Olaf Pinkenburg ; PhD^a ; Evita Bothur ; MSc^c ; Michael Lohoff ; MD^c ; Holger Garn ; PhD^a ; ^&lowast ; ; Petra Ina Pfefferle ; PhD ; DrPH^a ; ^&lowast ; ; Harald Renz ; MD^a ; ^&lowast ; ; ^{renzh@med.uni-marburg.de}
• 关键词：Epigenetics ; T cells ; experimental asthma
• 刊名：Journal of Allergy and Clinical Immunology
• 出版年：2012
• 期刊代码：158_00916749
• 类别：med
• 出版时间：June, 2012
• 卷：129
• 期：6
• 页码：1602-1610.e6
• 文件大小：1719 K

摘要

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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 Tb>Hb>1 and Tb>Hb>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 Tb>Hb>1 (IFNG promoter) or Tb>Hb>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-纬 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聽vitro and in聽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.