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

Wu, Chuan; Pot, Caroline; Apetoh, Lionel; Thalhamer, Theresa; Zhu, Bing; Murugaiyan, Gopal; Xiao, Sheng; Lee, Youjin; Rangachari, Manu; Yosef, Nir; Kuchroo, Vijay K

doi:10.1073/pnas.1211776110

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Title		Metallothioneins negatively regulate IL-27-induced type 1 regulatory T-cell differentiation
Authors		Wu, Chuan Pot, Caroline Apetoh, Lionel Thalhamer, Theresa Zhu, Bing Murugaiyan, Gopal Xiao, Sheng Lee, Youjin Rangachari, Manu Yosef, Nir Kuchroo, Vijay K show all authors [1 - 11]
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		Animals — Cell Differentiation — Cell Separation — Cells, Cultured — Encephalomyelitis, Autoimmune, Experimental/immunology — Flow Cytometry — Gene Expression Regulation — Humans — Interleukin-10/metabolism — Interleukin-17/metabolism — Metallothionein/metabolism — Mice — Mice, Inbred C57BL — Mice, Knockout — Phosphorylation — STAT1 Transcription Factor/metabolism — STAT3 Transcription Factor/metabolism — T-Lymphocytes, Regulatory/immunology/metabolism
Identifiers		DOI: 10.1073/pnas.1211776110 PMID: 23630250
Full text		Article (Published version) (724 Kb) - Free access
Structures		Faculté de médecine / Section de médecine fondamentale / Département de pathologie et immunologie
Research group		Groupe Pot-Kreis Caroline (931)
Project		Swiss National Science Foundation: PASMA—118720/1
Citation (ISO format)		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