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

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 controll...

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Veröffentlicht in:PloS one 2016-04, Vol.11 (4), p.e0153682-e0153682
Hauptverfasser: Goldstein, Jérémie D, Burlion, Aude, Zaragoza, Bruno, Sendeyo, Kélhia, Polansky, Julia K, Huehn, Jochen, Piaggio, Eliane, Salomon, Benoit L, Marodon, Gilles
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container_volume 11
creator Goldstein, Jérémie D
Burlion, Aude
Zaragoza, Bruno
Sendeyo, Kélhia
Polansky, Julia K
Huehn, Jochen
Piaggio, Eliane
Salomon, Benoit L
Marodon, Gilles
description 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.
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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. 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subjects Animals
Biology and life sciences
CD25 antigen
Cellular signal transduction
Conserved sequence
Cycloheximide
Demethylation
DNA Methylation - drug effects
Forkhead Transcription Factors - genetics
Forkhead Transcription Factors - metabolism
Foxp3 protein
Gene expression
Gene Expression Regulation - drug effects
Genetic aspects
Human health and pathology
Humans
Immunology
Immunoregulation
Infectious diseases
Interleukin 2
Introns - genetics
Janus Kinase 3 - antagonists & inhibitors
Janus Kinase 3 - metabolism
Life Sciences
Lymphocytes
Lymphocytes T
Medicine and health sciences
Mice
MicroRNAs
Mutation
Pharmacology
Phosphorylation
Physiological aspects
Protein Kinase Inhibitors - pharmacology
Proteins
Reduction
Research and Analysis Methods
Restoration
RNA, Messenger - genetics
RNA, Messenger - metabolism
Signal transduction
Signal Transduction - drug effects
Signaling
Stat5 protein
STAT5 Transcription Factor - metabolism
T cells
T-Lymphocytes, Regulatory - cytology
T-Lymphocytes, Regulatory - drug effects
T-Lymphocytes, Regulatory - metabolism
Transcription factors
title Inhibition of the JAK/STAT Signaling Pathway in Regulatory T Cells Reveals a Very Dynamic Regulation of Foxp3 Expression
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