title: β8 Integrin Expression and Activation of TGF-β by Intestinal Dendritic Cells Are Determined by Both Tissue Microenvironment and Cell Lineage.
abstract: Activation of TGF-β by dendritic cells (DCs) expressing αvβ8 integrin is essential for the generation of intestinal regulatory T cells (Tregs) that in turn promote tolerance to intestinal Ags. We have recently shown that αvβ8 integrin is preferentially expressed by CD103(+) DCs and confers their ability to activate TGF-β and generate Tregs. However, how these DCs become specialized for this vital function is unknown. In this study, we show that β8 expression is controlled by a combination of factors that include DC lineage and signals derived from the tissue microenvironment and microbiota. Specifically, our data demonstrate that TGF-β itself, along with retinoic acid and TLR signaling, drives expression of αvβ8 in DCs. However, these signals only result in high levels of β8 expression in cells of the cDC1 lineage, CD8α(+), or CD103(+)CD11b(-) DCs, and this is associated with epigenetic changes in the Itgb8 locus. Together, these data provide a key illustrative example of how microenvironmental factors and cell lineage drive the generation of regulatory αvβ8-expressing DCs specialized for activation of TGF-β to facilitate Treg generation.
authors.affiliation: CIRI, Centre International de Recherche en Infectiologie, Université de Lyon, 69365 Lyon, France; INSERM, U1111, 69007 Lyon, France; Ecole Normale Supérieure de Lyon, 69007 Lyon, France; Université Claude Bernard Lyon 1, Centre International de Recherche en Infectiologie, Lyon, France; CNRS, UMR5308, 69365 Lyon, France;
authors.forename: Mathilde
authors.initials: M
authors.lastname: Boucard-Jourdin
authors.affiliation: Benaroya Research Institute, Seattle, WA 98101;
authors.forename: David
authors.identifier: 0000-0002-2936-1649
authors.initials: D
authors.lastname: Kugler
authors.affiliation: CIRI, Centre International de Recherche en Infectiologie, Université de Lyon, 69365 Lyon, France; INSERM, U1111, 69007 Lyon, France; Ecole Normale Supérieure de Lyon, 69007 Lyon, France; Université Claude Bernard Lyon 1, Centre International de Recherche en Infectiologie, Lyon, France; CNRS, UMR5308, 69365 Lyon, France;
authors.forename: Marie-Laure
authors.identifier: 0000-0002-0861-1565
authors.initials: ML
authors.lastname: Endale Ahanda
authors.affiliation: CIRI, Centre International de Recherche en Infectiologie, Université de Lyon, 69365 Lyon, France; INSERM, U1111, 69007 Lyon, France; Ecole Normale Supérieure de Lyon, 69007 Lyon, France; Université Claude Bernard Lyon 1, Centre International de Recherche en Infectiologie, Lyon, France; CNRS, UMR5308, 69365 Lyon, France;
authors.forename: Sébastien
authors.initials: S
authors.lastname: This
authors.affiliation: Centro de Genómica y Bioinformática, Facultad de Ciencias, Universidad Mayor, Santiago 8580745, Chile;
authors.forename: Jaime
authors.identifier: 0000-0002-3927-1399
authors.initials: J
authors.lastname: De Calisto
authors.affiliation: Medical Research Council Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, United Kingdom; and.
authors.forename: Ailiang
authors.identifier: 0000-0002-6488-156X
authors.initials: A
authors.lastname: Zhang
authors.affiliation: Gastrointestinal Unit, Massachusetts General Hospital, Boston, MA 02114.
authors.forename: J Rodrigo
authors.identifier: 0000-0001-8819-0950
authors.initials: JR
authors.lastname: Mora
authors.affiliation: Benaroya Research Institute, Seattle, WA 98101;
authors.forename: Lynda M
authors.initials: LM
authors.lastname: Stuart
authors.affiliation: Medical Research Council Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, United Kingdom; and.
authors.forename: John
authors.identifier: 0000-0003-2079-1586
authors.initials: J
authors.lastname: Savill
authors.affiliation: Benaroya Research Institute, Seattle, WA 98101;
authors.forename: Adam
authors.initials: A
authors.lastname: Lacy-Hulbert
authors.affiliation: CIRI, Centre International de Recherche en Infectiologie, Université de Lyon, 69365 Lyon, France; INSERM, U1111, 69007 Lyon, France; Ecole Normale Supérieure de Lyon, 69007 Lyon, France; Université Claude Bernard Lyon 1, Centre International de Recherche en Infectiologie, Lyon, France; CNRS, UMR5308, 69365 Lyon, France; helena.paidassi@inserm.fr.
authors.forename: Helena
authors.initials: H
authors.lastname: Paidassi
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology; D002454:Cell Differentiation; D019070:Cell Lineage; D060833:Cellular Microenvironment; D003713:Dendritic Cells / Q000276:immunology* / Q000502:physiology; D039001:Integrin alpha Chains / Q000235:genetics / Q000276:immunology; D039641:Integrin beta Chains / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D007422:Intestines / Q000166:cytology* / Q000276:immunology; D051379:Mice; D050378:T-Lymphocytes, Regulatory / Q000502:physiology; D051193:Toll-Like Receptors / Q000276:immunology / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D014212:Tretinoin / Q000378:metabolism
chemical_list: D015703:Antigens, CD; D039001:Integrin alpha Chains; D039641:Integrin beta Chains; D051193:Toll-Like Receptors; D016212:Transforming Growth Factor beta; C091367:alpha E integrins; C094865:integrin beta8; D014212:Tretinoin