title: Critical role of all-trans retinoic acid in stabilizing human natural regulatory T cells under inflammatory conditions.
abstract: Recent studies have demonstrated that thymus-derived naturally occurring CD4(+)Foxp3(+) regulatory T cells (Tregs) in human and mouse may be unstable and dysfunctional in the presence of proinflammatory cytokines. All-trans RA (atRA), the active derivative of vitamin A, has been shown to regulate Treg and T effector cell differentiation. We hypothesize atRA stabilizes human natural Tregs (nTregs) under inflammatory conditions. atRA prevents human nTregs from converting to Th1 and/or Th17 cells and sustains their Foxp3 expression and suppressive function in vitro or in vivo following encounters with IL-1 and IL-6. Interestingly, adoptive transfer of human nTregs pretreated with atRA significantly enhanced their suppressive effects on xenograft-vs.-host diseases (xGVHDs), and atRA- but not rapamycin-pretreated nTregs sustained the functional activity against xGVHD after stimulation with IL-1/IL-6. atRA suppresses IL-1 receptor (IL-1R) up-regulation, accelerates IL-6R down-regulation, and diminishes their signaling events as well as prevents the up-regulation of STIP1 homology and U-Box containing protein 1 on Foxp3(+) cells following IL-1/IL-6 stimulation. atRA also increases histone acetylation on Foxp3 gene promoter and CpG demethylation in the region of Foxp3 locus (i.e., Treg-specific demethylated region). These results strongly implicate that nTregs primed with atRA may represent a novel treatment strategy to control established chronic immune-mediated autoimmune and inflammatory diseases.
authors.affiliation: Department of Liver Surgery, First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China;Division of Rheumatology and Immunology, University of Southern California, Los Angeles, CA 90033; szheng1@hmc.psu.edu lvling@njmu.edu.cn.
authors.forename: Ling
authors.initials: L
authors.lastname: Lu
authors.affiliation: Division of Rheumatology and Immunology, University of Southern California, Los Angeles, CA 90033;Immune Tolerance Center, Shanghai East Hospital at Tongji University, Shanghai 200120, China; szheng1@hmc.psu.edu lvling@njmu.edu.cn.
authors.forename: Qin
authors.initials: Q
authors.lastname: Lan
authors.affiliation: Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai 200025, China; szheng1@hmc.psu.edu lvling@njmu.edu.cn.
authors.forename: Zhiyuan
authors.initials: Z
authors.lastname: Li
authors.affiliation: Division of Rheumatology and Immunology, University of Southern California, Los Angeles, CA 90033;Immune Tolerance Center, Shanghai East Hospital at Tongji University, Shanghai 200120, China;
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Department of Liver Surgery, First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China;Division of Rheumatology and Immunology, University of Southern California, Los Angeles, CA 90033;
authors.forename: Jian
authors.initials: J
authors.lastname: Gu
authors.affiliation: Division of Rheumatology and Immunology, University of Southern California, Los Angeles, CA 90033;
authors.forename: Qiang
authors.initials: Q
authors.lastname: Li
authors.affiliation: Division of Rheumatology and Immunology, University of Southern California, Los Angeles, CA 90033;
authors.forename: Julie
authors.initials: J
authors.lastname: Wang
authors.affiliation: Division of Rheumatology and Immunology, University of Southern California, Los Angeles, CA 90033;
authors.forename: Maogen
authors.initials: M
authors.lastname: Chen
authors.affiliation: Division of Rheumatology and Immunology, University of Southern California, Los Angeles, CA 90033;
authors.forename: Ya
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Immune Tolerance Center, Shanghai East Hospital at Tongji University, Shanghai 200120, China;
authors.forename: Yi
authors.initials: Y
authors.lastname: Shen
authors.affiliation: Research Service, Veterans Affairs Medical Center, Memphis, TN 38163;
authors.forename: David D
authors.initials: DD
authors.lastname: Brand
authors.affiliation: Molecular Immunology and Embryology, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 6218, University of Orléans, 45071 Orleans, France; and.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Ryffel
authors.affiliation: Division of Rheumatology and Immunology, University of Southern California, Los Angeles, CA 90033;
authors.forename: David A
authors.initials: DA
authors.lastname: Horwitz
authors.affiliation: Division of Rheumatology and Immunology, University of Southern California, Los Angeles, CA 90033;
authors.forename: Francisco P
authors.initials: FP
authors.lastname: Quismorio
authors.affiliation: Immune Tolerance Center, Shanghai East Hospital at Tongji University, Shanghai 200120, China;
authors.forename: Zhongmin
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai 200025, China;
authors.forename: Bin
authors.initials: B
authors.lastname: Li
authors.affiliation: Division of Rheumatology, Department of Medicine, Penn State Milton S. Hershey Medical Center, Hershey, PA 17033.
authors.forename: Nancy J
authors.initials: NJ
authors.lastname: Olsen
authors.affiliation: Division of Rheumatology and Immunology, University of Southern California, Los Angeles, CA 90033;Immune Tolerance Center, Shanghai East Hospital at Tongji University, Shanghai 200120, China;Division of Rheumatology, Department of Medicine, Penn State Milton S. Hershey Medical Center, Hershey, PA 17033 szheng1@hmc.psu.edu lvling@njmu.edu.cn.
authors.forename: Song Guo
authors.initials: SG
authors.lastname: Zheng
mesh_terms: D001483:Base Sequence; D016207:Cytokines / Q000502:physiology; D017931:DNA Primers; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000473:pathology*; D007375:Interleukin-1 / Q000502:physiology; D015850:Interleukin-6 / Q000502:physiology; D060888:Real-Time Polymerase Chain Reaction; D017472:Receptors, Interleukin-1 / Q000378:metabolism; D019947:Receptors, Interleukin-6 / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology; D014212:Tretinoin / Q000494:pharmacology*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
chemical_list: D016207:Cytokines; D017931:DNA Primers; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D007375:Interleukin-1; D015850:Interleukin-6; D017472:Receptors, Interleukin-1; D019947:Receptors, Interleukin-6; D014212:Tretinoin; D044767:Ubiquitin-Protein Ligases
keywords: Treg cells; X-GVHD; epigenetic regulation; epigenetics; inflammation
references.citation: J Exp Med. 2012 Sep 24;209(10):1713-22, S1-19
references.pmid: 22966003
references.citation: Science. 2003 Feb 14;299(5609):1057-61
references.pmid: 12522256
references.citation: J Biol Chem. 2007 May 4;282(18):13552-60
references.pmid: 17337443
references.citation: PLoS One. 2011;6(9):e24590
references.pmid: 21931768
references.citation: Haematologica. 2013 Aug;98(8):1291-9
references.pmid: 23242600
references.citation: EMBO J. 1999 Oct 15;18(20):5601-8
references.pmid: 10523304
references.citation: Science. 2010 Sep 24;329(5999):1667-71
references.pmid: 20929851
references.citation: J Exp Med. 2006 Jun 12;203(6):1459-70
references.pmid: 16717113
references.citation: J Immunol. 2008 Dec 15;181(12):8209-13
references.pmid: 19050237
references.citation: Eur J Immunol. 2009 Apr;39(4):1088-97
references.pmid: 19283780
references.citation: Blood. 2006 Jul 1;108(1):253-61
references.pmid: 16537805
references.citation: J Mol Cell Biol. 2010 Jun;2(3):164-9
references.pmid: 20430855
references.citation: J Immunol. 2010 Apr 1;184(7):3433-41
references.pmid: 20181882
references.citation: J Immunol. 2008 Jun 1;180(11):7112-6
references.pmid: 18490709
references.citation: J Interferon Cytokine Res. 2006 Oct;26(10):739-47
references.pmid: 17032168
references.citation: Nat Immunol. 2009 Sep;10(9):1000-7
references.pmid: 19633673
references.citation: Nat Immunol. 2003 Apr;4(4):337-42
references.pmid: 12612581
references.citation: Blood. 2009 May 21;113(21):5125-33
references.pmid: 19299332
references.citation: J Mol Med (Berl). 2010 Oct;88(10):1029-40
references.pmid: 20574810
references.citation: Nat Rev Immunol. 2009 Feb;9(2):83-9
references.pmid: 19114986
references.citation: J Immunol. 2010 Sep 1;185(5):2675-9
references.pmid: 20679534
references.citation: J Immunol. 2009 Jan 1;182(1):259-73
references.pmid: 19109157
references.citation: Blood. 1986 May;67(5):1273-80
references.pmid: 3008888
references.citation: Nat Immunol. 2003 Apr;4(4):330-6
references.pmid: 12612578
references.citation: Nature. 2010 Feb 11;463(7282):808-12
references.pmid: 20072126
references.citation: J Interferon Cytokine Res. 2003 Apr;23(4):183-92
references.pmid: 12856330
references.citation: PLoS Biol. 2007 Feb;5(2):e38
references.pmid: 17298177
references.citation: J Immunol. 2007 Jun 1;178(11):6725-9
references.pmid: 17513718
references.citation: Eur J Immunol. 2012 May;42(5):1174-9
references.pmid: 22539291
references.citation: Immunity. 2013 Aug 22;39(2):272-85
references.pmid: 23973223
references.citation: Int Immunol. 2003 Aug;15(8):1017-25
references.pmid: 12882839
references.citation: Transplantation. 2009 Jun 15;87(11):1654-8
references.pmid: 19502956
references.citation: Blood. 2008 Sep 15;112(6):2340-52
references.pmid: 18617638
references.citation: J Exp Med. 2012 Sep 24;209(10):1723-42, S1
references.pmid: 22966001
references.citation: J Immunol. 2010 Apr 15;184(8):4295-306
references.pmid: 20304828
references.citation: Immunity. 2012 Feb 24;36(2):262-75
references.pmid: 22326580
references.citation: J Interferon Cytokine Res. 2003 Sep;23(9):513-22
references.pmid: 14565860
references.citation: Nature. 2007 Feb 15;445(7129):766-70
references.pmid: 17220876
references.citation: Science. 2007 Jul 13;317(5835):256-60
references.pmid: 17569825
references.citation: Proc Natl Acad Sci U S A. 2014 Apr 8;111(14):5289-94
references.pmid: 24706905
references.citation: J Mol Cell Biol. 2012 Feb;4(1):22-8
references.pmid: 22107826
references.citation: Blood. 2009 Apr 30;113(18):4240-9
references.pmid: 19171879
references.citation: PLoS One. 2011 Jan 06;6(1):e15868
references.pmid: 21253593
references.citation: Nat Protoc. 2008;3(6):1032-45
references.pmid: 18536650
references.citation: Immunity. 2009 Jun 19;30(6):899-911
references.pmid: 19464196