title: Integrin αvβ8-Mediated TGF-β Activation by Effector Regulatory T Cells Is Essential for Suppression of T-Cell-Mediated Inflammation.
abstract: Regulatory T (Treg) cells play a pivotal role in suppressing self-harmful T cell responses, but how Treg cells mediate suppression to maintain immune homeostasis and limit responses during inflammation is unclear. Here we show that effector Treg cells express high amounts of the integrin αvβ8, which enables them to activate latent transforming growth factor-β (TGF-β). Treg-cell-specific deletion of integrin αvβ8 did not result in a spontaneous inflammatory phenotype, suggesting that this pathway is not important in Treg-cell-mediated maintenance of immune homeostasis. However, Treg cells lacking expression of integrin αvβ8 were unable to suppress pathogenic T cell responses during active inflammation. Thus, our results identify a mechanism by which Treg cells suppress exuberant immune responses, highlighting a key role for effector Treg-cell-mediated activation of latent TGF-β in suppression of self-harmful T cell responses during active inflammation.
authors.affiliation: Manchester Collaborative Centre for Inflammation Research, University of Manchester, Manchester M13 9NT, UK; Wellcome Trust Centre for Cell-Matrix Research, Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, UK; Manchester Immunology Group, Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, UK. Electronic address: john.j.worthington@manchester.ac.uk.
authors.forename: John J
authors.initials: JJ
authors.lastname: Worthington
authors.affiliation: Manchester Collaborative Centre for Inflammation Research, University of Manchester, Manchester M13 9NT, UK; Wellcome Trust Centre for Cell-Matrix Research, Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, UK; Manchester Immunology Group, Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, UK.
authors.forename: Aoife
authors.initials: A
authors.lastname: Kelly
authors.affiliation: Manchester Collaborative Centre for Inflammation Research, University of Manchester, Manchester M13 9NT, UK; Wellcome Trust Centre for Cell-Matrix Research, Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, UK; Manchester Immunology Group, Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, UK.
authors.forename: Catherine
authors.initials: C
authors.lastname: Smedley
authors.affiliation: Immunology Virology and Inflammation Department, CRCL, UMR INSERM1052, CNRS 5286, Centre Léon Bérard, 28 rue Laennec, 69373 Cedex 08 Lyon, France; Université Lyon 1, 69000 Lyon, France; Labex DEVweCAN, 69008 Lyon, France; TGFβ and Immuno-evasion Group, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors.forename: David
authors.initials: D
authors.lastname: Bauché
authors.affiliation: Gastroenterology Unit, Manchester Royal Infirmary, Central Manchester University Hospital NHS Foundation Trust, Manchester M13 9WL, UK.
authors.forename: Simon
authors.initials: S
authors.lastname: Campbell
authors.affiliation: Immunology Virology and Inflammation Department, CRCL, UMR INSERM1052, CNRS 5286, Centre Léon Bérard, 28 rue Laennec, 69373 Cedex 08 Lyon, France; Université Lyon 1, 69000 Lyon, France; Labex DEVweCAN, 69008 Lyon, France; TGFβ and Immuno-evasion Group, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors.forename: Julien C
authors.initials: JC
authors.lastname: Marie
authors.affiliation: Manchester Collaborative Centre for Inflammation Research, University of Manchester, Manchester M13 9NT, UK; Wellcome Trust Centre for Cell-Matrix Research, Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, UK; Manchester Immunology Group, Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, UK. Electronic address: mark.travis@manchester.ac.uk.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Travis
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D003092:Colitis / Q000276:immunology; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000276:immunology; D006801:Humans; D007249:Inflammation / Q000276:immunology*; D018836:Inflammation Mediators / Q000276:immunology; D016023:Integrins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018448:Models, Immunological; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000276:immunology*
chemical_list: D018836:Inflammation Mediators; D016023:Integrins; D016212:Transforming Growth Factor beta; C403414:integrin alphavbeta8