Inhibition of the JAK/STAT Signaling Pathway in Regulatory T Cells Reveals a Very Dynamic Regulation of Foxp3 Expression.

2.50
Hdl Handle:
http://hdl.handle.net/10033/620051
Title:
Inhibition of the JAK/STAT Signaling Pathway in Regulatory T Cells Reveals a Very Dynamic Regulation of Foxp3 Expression.
Authors:
Goldstein, Jérémie D; Burlion, Aude; Zaragoza, Bruno; Sendeyo, Kélhia; Polansky, Julia K; Huehn, Jochen; Piaggio, Eliane; Salomon, Benoit L; Marodon, Gilles
Abstract:
The IL-2/JAK3/STAT-5 signaling pathway is involved on the initiation and maintenance of the transcription factor Foxp3 in regulatory T cells (Treg) and has been associated with demethylation of the intronic Conserved Non Coding Sequence-2 (CNS2). However, the role of the JAK/STAT pathway in controlling Foxp3 in the short term has been poorly investigated. Using two different JAK/STAT pharmacological inhibitors, we observed a detectable loss of Foxp3 after 10 min. of treatment that affected 70% of the cells after one hour. Using cycloheximide, a general inhibitor of mRNA translation, we determined that Foxp3, but not CD25, has a high turnover in IL-2 stimulated Treg. This reduction was correlated with a rapid reduction of Foxp3 mRNA. This loss of Foxp3 was associated with a loss in STAT-5 binding to the CNS2, which however remains demethylated. Consequently, Foxp3 expression returns to normal level upon restoration of basal JAK/STAT signaling in vivo. Reduced expression of several genes defining Treg identity was also observed upon treatment. Thus, our results demonstrate that Foxp3 has a rapid turn over in Treg partly controlled at the transcriptional level by the JAK/STAT pathway.
Affiliation:
Helmholtz Centre for infection research, Inhoffenstr. 7, 38124 Braunschweig, Germany.
Citation:
Inhibition of the JAK/STAT Signaling Pathway in Regulatory T Cells Reveals a Very Dynamic Regulation of Foxp3 Expression. 2016, 11 (4):e0153682 PLoS ONE
Journal:
PloS one
Issue Date:
2016
URI:
http://hdl.handle.net/10033/620051
DOI:
10.1371/journal.pone.0153682
PubMed ID:
27077371
Type:
Article
Language:
en
ISSN:
1932-6203
Appears in Collections:
publications of the division experimentelle Immunologie (EXIM)

Full metadata record

DC FieldValue Language
dc.contributor.authorGoldstein, Jérémie Den
dc.contributor.authorBurlion, Audeen
dc.contributor.authorZaragoza, Brunoen
dc.contributor.authorSendeyo, Kélhiaen
dc.contributor.authorPolansky, Julia Ken
dc.contributor.authorHuehn, Jochenen
dc.contributor.authorPiaggio, Elianeen
dc.contributor.authorSalomon, Benoit Len
dc.contributor.authorMarodon, Gillesen
dc.date.accessioned2016-09-13T07:57:50Z-
dc.date.available2016-09-13T07:57:50Z-
dc.date.issued2016-
dc.identifier.citationInhibition of the JAK/STAT Signaling Pathway in Regulatory T Cells Reveals a Very Dynamic Regulation of Foxp3 Expression. 2016, 11 (4):e0153682 PLoS ONEen
dc.identifier.issn1932-6203-
dc.identifier.pmid27077371-
dc.identifier.doi10.1371/journal.pone.0153682-
dc.identifier.urihttp://hdl.handle.net/10033/620051-
dc.description.abstractThe IL-2/JAK3/STAT-5 signaling pathway is involved on the initiation and maintenance of the transcription factor Foxp3 in regulatory T cells (Treg) and has been associated with demethylation of the intronic Conserved Non Coding Sequence-2 (CNS2). However, the role of the JAK/STAT pathway in controlling Foxp3 in the short term has been poorly investigated. Using two different JAK/STAT pharmacological inhibitors, we observed a detectable loss of Foxp3 after 10 min. of treatment that affected 70% of the cells after one hour. Using cycloheximide, a general inhibitor of mRNA translation, we determined that Foxp3, but not CD25, has a high turnover in IL-2 stimulated Treg. This reduction was correlated with a rapid reduction of Foxp3 mRNA. This loss of Foxp3 was associated with a loss in STAT-5 binding to the CNS2, which however remains demethylated. Consequently, Foxp3 expression returns to normal level upon restoration of basal JAK/STAT signaling in vivo. Reduced expression of several genes defining Treg identity was also observed upon treatment. Thus, our results demonstrate that Foxp3 has a rapid turn over in Treg partly controlled at the transcriptional level by the JAK/STAT pathway.en
dc.language.isoenen
dc.rights.urihttp://creativecommons.org/licenses/by-nc-sa/4.0/*
dc.subject.meshAnimalsen
dc.subject.meshDNA Methylationen
dc.subject.meshForkhead Transcription Factorsen
dc.subject.meshGene Expression Regulationen
dc.subject.meshHumansen
dc.subject.meshIntronsen
dc.subject.meshJanus Kinase 3en
dc.subject.meshMiceen
dc.subject.meshProtein Kinase Inhibitorsen
dc.subject.meshRNA, Messengeren
dc.subject.meshSTAT5 Transcription Factoren
dc.subject.meshSignal Transductionen
dc.subject.meshT-Lymphocytes, Regulatoryen
dc.titleInhibition of the JAK/STAT Signaling Pathway in Regulatory T Cells Reveals a Very Dynamic Regulation of Foxp3 Expression.en
dc.typeArticleen
dc.contributor.departmentHelmholtz Centre for infection research, Inhoffenstr. 7, 38124 Braunschweig, Germany.en
dc.identifier.journalPloS oneen

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