title: Metallothioneins negatively regulate IL-27-induced type 1 regulatory T-cell differentiation.
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.
authors: Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors: Chuan
authors: C
authors: Wu
authors: Caroline
authors: C
authors: Pot
authors: Lionel
authors: L
authors: Apetoh
authors: Theresa
authors: T
authors: Thalhamer
authors: Bing
authors: B
authors: Zhu
authors: Gopal
authors: G
authors: Murugaiyan
authors: Sheng
authors: S
authors: Xiao
authors: Youjin
authors: Y
authors: Lee
authors: Manu
authors: M
authors: Rangachari
authors: Nir
authors: N
authors: Yosef
authors: Vijay K
authors: VK
authors: Kuchroo
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002469:Cell Separation; D002478:Cells, Cultured; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D006801:Humans; D016753:Interleukin-10 / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism*; D008668:Metallothionein / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010766:Phosphorylation; D050794:STAT1 Transcription Factor / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism*
chemical_list: D020381:Interleukin-17; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; C494080:Stat1 protein, mouse; C494087:Stat3 protein, mouse; D016753:Interleukin-10; D008668:Metallothionein
references: Biochem J. 1999 Jan 1;337 ( Pt 1):59-65
references: 9854025
references: Immunity. 2009 Aug 21;31(2):209-19
references: 19646904
references: Nat Immunol. 2006 Sep;7(9):937-45
references: 16906166
references: Neuroscience. 2005;132(4):1135-49
references: 16078373
references: Mol Cell Biol. 2001 Dec;21(24):8301-17
references: 11713267
references: J Neurosci Res. 2003 Jun 1;72(5):574-86
references: 12749022
references: Annu Rev Biochem. 1986;55:913-51
references: 3527054
references: Nat Immunol. 2010 Sep;11(9):854-61
references: 20676095
references: J Neuroimmunol. 2001 Oct 1;119(2):248-60
references: 11585628
references: Recent Pat Anticancer Drug Discov. 2011 May;6(2):178-85
references: 21449882
references: Immunol Rev. 2006 Aug;212:28-50
references: 16903904
references: Nat Immunol. 2012 Oct;13(10):991-9
references: 22961052
references: J Immunol. 2009 Jul 15;183(2):797-801
references: 19570826
references: Immunol Lett. 2011 Apr 30;136(1):21-8
references: 21115047
references: Clin Exp Immunol. 2002 Aug;129(2):232-9
references: 12165078
references: J Exp Med. 2002 Mar 4;195(5):603-16
references: 11877483
references: Proc Natl Acad Sci U S A. 2006 May 23;103(21):8137-42
references: 16698929
references: J Exp Med. 2005 Jan 17;201(2):233-40
references: 15657292
references: Nat Protoc. 2006;1(4):1810-9
references: 17487163
references: J Immunol. 1999 Sep 1;163(5):2403-9
references: 10452974
references: Nat Immunol. 2007 Dec;8(12):1390-7
references: 17994024
references: Cell Mol Life Sci. 2003 Jan;60(1):185-97
references: 12613667
references: Nat Immunol. 2007 Dec;8(12):1372-9
references: 17994023
references: Cancer Res. 1998 Jun 1;58(11):2335-8
references: 9622069
references: Immunity. 2006 Dec;25(6):941-52
references: 17137799
references: FEBS Lett. 1996 May 13;386(1):1-4
references: 8635592
references: Nat Immunol. 2007 Dec;8(12):1380-9
references: 17994022
references: J Immunol. 2009 May 15;182(10):6226-36
references: 19414776
references: Cancer Res. 2009 Oct 1;69(19):7756-66
references: 19789353
references: Int Immunol. 2010 May;22(5):375-86
references: 20215335