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Metallothioneins negatively regulate IL-27-induced type 1 regulatory T-cell differentiation

Wu, Chuan
Apetoh, Lionel
Thalhamer, Theresa
Zhu, Bing
Murugaiyan, Gopal
Xiao, Sheng
Lee, Youjin
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Published in Proceedings of the National Academy of Sciences of the United States of America. 2013, vol. 110, no. 19, p. 7802-7
Abstract IL-27-induced type 1 regulatory T (Tr1) cells suppress autoimmunity by producing IL-10. Signal transducer and activator of transcription (STAT) 1 and STAT3 have been described as key transcription factors that promote IL-10 secretion from Tr1 cells induced by IL-27. However, the molecular pathways for negatively regulating Tr1 cell differentiation remain elusive. Here, we show that IL-27 induces metallothioneins (MTs) that in turn prevent Tr1 cell development. MT expression leads to the reduction of STAT1 and STAT3 phosphorylation under Tr1 differentiation condition, resulting in impaired IL-10 production. Accordingly, Tr1 cells derived from MT-deficient mice showed an increased ability to produce IL-10 and potently suppress experimental autoimmune encephalomyelitis upon adoptive transfer. Moreover, activation of STAT1 and/or STAT3 can overcome the suppression of IL-10 by MTs, indicating a dynamic balance between STATs and MTs in regulating IL-10 during Tr1 cell differentiation.
Keywords AnimalsCell DifferentiationCell SeparationCells, CulturedEncephalomyelitis, Autoimmune, Experimental/immunologyFlow CytometryGene Expression RegulationHumansInterleukin-10/metabolismInterleukin-17/metabolismMetallothionein/metabolismMiceMice, Inbred C57BLMice, KnockoutPhosphorylationSTAT1 Transcription Factor/metabolismSTAT3 Transcription Factor/metabolismT-Lymphocytes, Regulatory/immunology/metabolism
PMID: 23630250
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Research group Groupe Pot-Kreis Caroline (931)
Swiss National Science Foundation: PASMA—118720/1
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WU, Chuan et al. Metallothioneins negatively regulate IL-27-induced type 1 regulatory T-cell differentiation. In: Proceedings of the National Academy of Sciences of the United States of America, 2013, vol. 110, n° 19, p. 7802-7. doi: 10.1073/pnas.1211776110 https://archive-ouverte.unige.ch/unige:33008

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Deposited on : 2014-01-09

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