title: Inhibition of the JAK/STAT Signaling Pathway in Regulatory T Cells Reveals a Very Dynamic Regulation of Foxp3 Expression.
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.
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, UMR-S CR7, Centre d'Immunologie et des Maladies Infectieuses (CIMI), INSERM U1135, CNRS ERL 8255, Paris, France.
authors.forename: Jérémie D
authors.initials: JD
authors.lastname: Goldstein
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, UMR-S CR7, Centre d'Immunologie et des Maladies Infectieuses (CIMI), INSERM U1135, CNRS ERL 8255, Paris, France.
authors.forename: Aude
authors.initials: A
authors.lastname: Burlion
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, UMR-S CR7, Centre d'Immunologie et des Maladies Infectieuses (CIMI), INSERM U1135, CNRS ERL 8255, Paris, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Zaragoza
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, UMR-S CR7, Centre d'Immunologie et des Maladies Infectieuses (CIMI), INSERM U1135, CNRS ERL 8255, Paris, France.
authors.forename: Kélhia
authors.initials: K
authors.lastname: Sendeyo
authors.affiliation: Department of Experimental Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany.
authors.forename: Julia K
authors.initials: JK
authors.lastname: Polansky
authors.affiliation: Department of Experimental Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany.
authors.forename: Jochen
authors.initials: J
authors.lastname: Huehn
authors.affiliation: INSERM U932, Institut Curie, Paris, France.
authors.forename: Eliane
authors.initials: E
authors.lastname: Piaggio
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, UMR-S CR7, Centre d'Immunologie et des Maladies Infectieuses (CIMI), INSERM U1135, CNRS ERL 8255, Paris, France.
authors.forename: Benoit L
authors.initials: BL
authors.lastname: Salomon
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, UMR-S CR7, Centre d'Immunologie et des Maladies Infectieuses (CIMI), INSERM U1135, CNRS ERL 8255, Paris, France.
authors.forename: Gilles
authors.identifier: http://orcid.org/0000-0003-4889-6785
authors.initials: G
authors.lastname: Marodon
mesh_terms: D000818:Animals; D019175:DNA Methylation / Q000187:drug effects; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D007438:Introns / Q000235:genetics; D053616:Janus Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051379:Mice; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D050378:T-Lymphocytes, Regulatory / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism
chemical_list: C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D050799:STAT5 Transcription Factor; D053616:Janus Kinase 3