Valproate treatment of human cord blood CD4-positive effector T cells confers on them the molecular profile (microRNA signature and FOXP3 expression) of natural regulatory CD4-positive cells through inhibition of histone deacetylase.

Détails

ID Serval
serval:BIB_E05CE416154A
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
Valproate treatment of human cord blood CD4-positive effector T cells confers on them the molecular profile (microRNA signature and FOXP3 expression) of natural regulatory CD4-positive cells through inhibition of histone deacetylase.
Périodique
Journal of Biological Chemistry
Auteur(s)
Fayyad-Kazan H., Rouas R., Merimi M., El Zein N., Lewalle P., Jebbawi F., Mourtada M., Badran H., Ezzeddine M., Salaun B., Romero P., Burny A., Martiat P., Badran B.
ISSN
1083-351X[electronic], 0021-9258[linking]
Statut éditorial
Publié
Date de publication
2010
Volume
285
Numéro
27
Pages
20481-20491
Langue
anglais
Résumé
Regulatory T cells (Tregs) play a key role in immune system homeostasis and tolerance to antigens, thereby preventing autoimmunity, and may be partly responsible for the lack of an appropriate immune response against tumor cells. Although not sufficient, a high expression of forkhead box P3 (FOXP3) is necessary for their suppressive function. Recent reports have shown that histones deacetylase inhibitors increased FOXP3 expression in T cells. We therefore decided to investigate in non-Tregs CD4-positive cells, the mechanisms by which an aspecific opening of the chromatin could lead to an increased FOXP3 expression. We focused on binding of potentially activating transcription factors to the promoter region of FOXP3 and on modifications in the five miRs constituting the Tregs signature. Valproate treatment induced binding of Ets-1 and Ets-2 to the FOXP3 promoter and acted positively on its expression, by increasing the acetylation of histone H4 lysines. Valproate treatment also induced the acquisition of the miRs Tregs signature. To elucidate whether the changes in the miRs expression could be due to the increased FOXP3 expression, we transduced these non-Tregs with a FOXP3 lentiviral expression vector, and found no changes in miRs expression. Therefore, the modification in their miRs expression profile is not due to an increased expression of FOXP3 but directly results from histones deacetylase inhibition. Rather, the increased FOXP3 expression results from the additive effects of Ets factors binding and the change in expression level of miR-21 and miR-31. We conclude that valproate treatment of human non-Tregs confers on them a molecular profile similar to that of their regulatory counterpart.
Mots-clé
5' Untranslated Regions/genetics, CD4-Positive T-Lymphocytes/drug effects, CD4-Positive T-Lymphocytes/physiology, Cells, Cultured, Conserved Sequence, DNA Primers, Fetal Blood/immunology, Forkhead Transcription Factors/genetics, Histone Deacetylases/genetics, Histone Deacetylases/immunology, Humans, Infant, Newborn, MicroRNAs/genetics, Plasmids, Polymerase Chain Reaction/methods, Promoter Regions, Genetic, T-Lymphocytes/drug effects, T-Lymphocytes/immunology, T-Lymphocytes, Regulatory/drug effects, T-Lymphocytes, Regulatory/immunology, Transfection, Valproic Acid/pharmacology
Pubmed
Web of science
Open Access
Oui
Création de la notice
02/02/2011 11:27
Dernière modification de la notice
20/08/2019 17:04
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