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Β8 Integrin Expression and Activation of TGF-Β by Intestinal Dendritic

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Β8 Integrin Expression and Activation of TGF-Β by Intestinal Dendritic β8 Integrin Expression and Activation of TGF- β by Intestinal Dendritic Cells Are Determined by Both Tissue Microenvironment and Cell Lineage This information is current as of September 26, 2021. Mathilde Boucard-Jourdin, David Kugler, Marie-Laure Endale Ahanda, Sébastien This, Jaime De Calisto, Ailiang Zhang, J. Rodrigo Mora, Lynda M. Stuart, John Savill, Adam Lacy-Hulbert and Helena Paidassi J Immunol published online 1 August 2016 Downloaded from http://www.jimmunol.org/content/early/2016/07/30/jimmun ol.1600244 http://www.jimmunol.org/ Supplementary http://www.jimmunol.org/content/suppl/2016/07/30/jimmunol.160024 Material 4.DCSupplemental Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists by guest on September 26, 2021 • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2016 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published August 1, 2016, doi:10.4049/jimmunol.1600244 The Journal of Immunology b8 Integrin Expression and Activation of TGF-b by Intestinal Dendritic Cells Are Determined by Both Tissue Microenvironment and Cell Lineage Mathilde Boucard-Jourdin,*,†,‡,x,{,1 David Kugler,‖,1 Marie-Laure Endale Ahanda,*,†,‡,x,{ Se´bastien This,*,†,‡,x,{ Jaime De Calisto,# Ailiang Zhang,** J. Rodrigo Mora,†† Lynda M. Stuart,‖ John Savill,** Adam Lacy-Hulbert,‖,2 and Helena Paidassi*,†,‡,x,{,2 Activation of TGF-b by dendritic cells (DCs) expressing avb8 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 avb8 integrin is preferentially expressed by CD103+ DCs and confers their ability to activate TGF-b and generate Tregs. However, how these DCs become specialized for this vital function is unknown. In this study, we show that b8 expression is controlled by a combination of factors Downloaded from that include DC lineage and signals derived from the tissue microenvironment and microbiota. Specifically, our data demonstrate that TGF-b itself, along with retinoic acid and TLR signaling, drives expression of avb8 in DCs. However, these signals only result in high levels of b8 expression in cells of the cDC1 lineage, CD8a+, or CD103+CD11b2 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 avb8-expressing DCs specialized for activation of TGF-b to facilitate Treg generation. The Journal of Immunology, 2016, 197: 000–000. http://www.jimmunol.org/ endritic cells (DCs) serve a unique sentinel role in the (1, 2). Determining how DCs differentiate to carry out specialized body, surveying tissues, integrating peripheral cues, and functions is critical for our understanding of immunity in health and D instructing the adaptive immune system accordingly. DCs disease. can orchestrate powerful pathogen-directed immunity or regulate The intestine provides a particular challenge for the immune and suppress immune responses to self-associated or innocuous Ags, system, containing a high local concentration of microbes, includ- and the complexity of these roles is reflected in the diverse popula- ing commensals and potential pathogens, as well as diverse dietary tions of DCs found in different tissues and under different conditions and environmental Ags (3). To prevent inappropriate inflammatory by guest on September 26, 2021 responses to these mostly innocuous Ags, the mucosal immune *CIRI, Centre International de Recherche en Infectiologie, Universite´ de Lyon, system has robust immunoregulatory mechanisms that include 69365 Lyon, France; †INSERM, U1111, 69007 Lyon, France; ‡Ecole Normale Supe´r- regulatory lymphocytes, which reside in the mucosa and associ- ieure de Lyon, 69007 Lyon, France; xUniversite´ Claude Bernard Lyon 1, Centre International de Recherche en Infectiologie, Lyon, France; {CNRS, UMR5308, ated lymphoid organs and actively suppress immune responses to 69365 Lyon, France; ‖Benaroya Research Institute, Seattle, WA 98101; #Centro intestinal Ags (4). The best characterized of these are CD4+ Foxp3+ de Geno´mica y Bioinforma´tica, Facultad de Ciencias, Universidad Mayor, San- regulatory T cells (Tregs), which either originate in the thymus tiago 8580745, Chile; **Medical Research Council Centre for Inflammation Research, Queen’s Medical Research Institute, University of Edinburgh, Edinburgh (thymic or natural Tregs) or are generated in the periphery from EH16 4TJ, United Kingdom; and ††Gastrointestinal Unit, Massachusetts General naive CD4+ T cells (peripheral or adaptive Tregs). In the intestine, Hospital, Boston, MA 02114 peripheral Tregs are generated by DCs that constitutively acquire 1 M.B.-J. and D.K. contributed equally to this work. and present self and foreign Ags (5, 6), resulting in Ag-specific tol- 2 A.L.-H. and H.P. contributed equally to this work. erance (7). The generation of peripheral Tregs requires TGF-b,and ORCIDs: 0000-0002-2936-1649 (D.K.); 0000-0002-0861-1565 (M.-L.E.A.); 0000-0002- we and others have shown that an essential characteristic of DCs that 3927-1399 (J.D.C.); 0000-0002-6488-156X (A.Z.); 0000-0001-8819-0950 (J.R.M.); 0000-0003-2079-1586 (J.S.). generate Tregs is their ability to activate TGF-b from its inactive or Received for publication February 10, 2016. Accepted for publication June 30, 2016. latent precursor to an active form that can engage the TGF-b receptor This work was supported by Agence Nationale de la Recherche Grant ANR-13- (8, 9). This requires the action of a specific cell surface integrin, PDOC-0019, People Programme (Marie Sklodowska-Curie Actions) of the European avb8, and, underscoring the importance of this process, deletion of Union’s Seventh Framework Programme Research Executive Agency Grant PIIF- either the avorb8 subset from DCs results in failure to generate GA-2012-330432, the Mitchell Trust (to H.P.), National Institutes of Health Grant R01DK093695 (to A.L.-H.), a Crohn’s and Colitis Foundation of America grant intestinal Tregs and subsequent development of colitis (10, 11). (to A.L.-H.), and UK Medical Research Council Grant G0802069 (to J.S.). Recently, we have shown that expression of avb8 is tightly Address correspondence and reprint requests to Dr. Helena Paidassi, Centre Interna- regulated in DCs. Although the av subunit, the only known partner tional de Recherche en Infectiologie, 21, Avenue Tony Garnier, 69365 Lyon Cedex of b8 (12), is ubiquitously expressed, b8 expression is restricted to 07, France. E-mail address: [email protected] specific subsets of cells in the intestine (8). Under homeostatic The online version of this article contains supplemental material. conditions, avb8 is expressed predominantly on DCs from mes- Abbreviations used in this article: DC, dendritic cell; FL-DC, bone marrow–derived DC generated in the presence of Flt3-ligand; IRF, IFN regulatory factor; KO, knock- enteric lymph nodes (MLN) and intestinal lamina propria (LP) that out; LP, lamina propria; l-TGF-b, latent TGF-b; MLN, mesenteric lymph node; express the mucosal integrin aEb7 (CD103), conferring on these ODN, oligodeoxynucleotide; RA, retinoic acid; Treg, regulatory T cell; TRIF, Toll/ cells their preferential ability to activate TGF-b and generate Tregs IL-1R domain–containing adapter-inducting IFN-b; VAD, vitamin A–deficient. (8, 9). CD103+ DCs have previously been implicated in the gen- Copyright Ó 2016 by The American Association of Immunologists, Inc. 0022-1767/16/$30.00 eration of intestinal Tregs, which has also been attributed to their www.jimmunol.org/cgi/doi/10.4049/jimmunol.1600244 2 b8 INTEGRIN EXPRESSION IN DENDRITIC CELLS ability to synthesize all-trans retinoic acid (RA) that promotes Treg General Hospital). Tgfbr2fl/fl mice (B6.129S6-Tgfbr2tm1Hlm) were obtained from H. Moses (13) (Vanderbilt-Ingram Cancer Center, Nashville, TN). generation in the presence of TGF-b. These data therefore support IRES-eGFP the concept that subsets of intestinal DCs are specialized for gen- Foxp3 reporter mice were obtained from D. Kaiserlian (Centre In- ternational de Recherche en Infectiologie). All mice were on C57BL/6 eration of Tregs. However, the precise mechanisms by which this background, except for Tgfbr2-flox mice, which were on a mixed B6.129S6 population of DCs acquires this specialized ability to activate TGF-b background. Animal experiments were performed under appropriate licenses and how microenvironmental cues and cell lineage are integrated in within local and national guidelines for animal care. this process remain to be fully determined. DC isolation In this study, we set out to identify the signals that regulate b8 expression in intestinal DCs. We report that avb8 is expressed DCs from spleen, MLN, and LP were isolated as previously described (8). + 2 Bone marrow–derived DCs generated in the presence of Flt3-ligand (FL-DCs) preferentially on the CD103 CD11b subset of DCs in the MLNs, were cultured, as previously described (14). Briefly, bone marrow cells were and that expression is acquired in the LP. We show that signals cultured in the presence of 100 ng/ml recombinant Flt3-ligand (PeproTech, from the mucosal microenvironment, specifically TGF-b, RA, and Neuilly-sur-Seine, France). Fresh medium was added to the cultures on day 3 TLR agonists, together promote expression of b8 integrin in DCs and 6, and cells were harvested at day 9. FL-DC subsets were then sorted by and that inhibition of signaling through these pathways in mice flow cytometry, as indicated.
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