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Gata3 hypermethylation and Foxp3 hypomethylation are associated with sustained protection and bystander effect following epicutaneous immunotherapy in peanut‐sensitized mice
Author(s) -
Mondoulet L.,
Dioszeghy V.,
Busato F.,
Plaquet C.,
Dhelft V.,
Bethune K.,
Leclere L.,
Daviaud C.,
Ligouis M.,
Sampson H.,
Dupont C.,
Tost J.
Publication year - 2019
Publication title -
allergy
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.363
H-Index - 173
eISSN - 1398-9995
pISSN - 0105-4538
DOI - 10.1111/all.13479
Subject(s) - foxp3 , bystander effect , sensitization , dna methylation , immunology , immunotherapy , epigenetics , spleen , gata3 , biology , downregulation and upregulation , cancer research , transcription factor , immune system , gene expression , gene , genetics
Background Epicutaneous immunotherapy ( EPIT ) is a promising method for treating food allergies. In animal models, EPIT induces sustained unresponsiveness and prevents further sensitization mediated by Tregs. Here, we elucidate the mechanisms underlying the therapeutic effect of EPIT , by characterizing the kinetics of DNA methylation changes in sorted cells from spleen and blood and by evaluating its persistence and bystander effect compared to oral immunotherapy ( OIT ). Methods BALB /c mice orally sensitized to peanut proteins ( PPE ) were treated by EPIT using a PPE ‐patch or by PPE ‐ OIT . Another set of peanut‐sensitized mice treated by EPIT or OIT were sacrificed following a protocol of sensitization to OVA . DNA methylation was analyzed during immunotherapy and 8 weeks after the end of treatment in sorted cells from spleen and blood by pyrosequencing. Humoral and cellular responses were measured during and after immunotherapy. Results Analyses showed a significant hypermethylation of the Gata3 promoter detectable only in Th2 cells for EPIT from the 4th week and a significant hypomethylation of the Foxp3 promoter in CD 62L + Tregs, which was sustained only for EPIT . In addition, mice treated with EPIT were protected from subsequent sensitization and maintained the epigenetic signature characteristic for EPIT . Conclusions Our study demonstrates that EPIT leads to a unique and stable epigenetic signature in specific T‐cell compartments with downregulation of Th2 key regulators and upregulation of Treg transcription factors, likely explaining the sustainability of protection and the observed bystander effect.