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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2020,6,2]]},"abstract":"<jats:p>\n                    In multiple sclerosis (MS), Th17 cells are critical drivers of autoimmune central nervous system (CNS) inflammation and demyelination. Th17 cells exhibit functional heterogeneity fostering both pathogenic and nonpathogenic, tissue-protective functions. Still, the factors that control Th17 pathogenicity remain incompletely defined. Here, using experimental autoimmune encephalomyelitis, an established mouse MS model, we report that therapeutic administration of activin-A ameliorates disease severity and alleviates CNS immunopathology and demyelination, associated with decreased activation of Th17 cells. In fact, activin-A signaling through activin-like kinase-4 receptor represses pathogenic transcriptional programs in Th17-polarized cells, while it enhances antiinflammatory gene modules. Whole-genome profiling and in vivo functional studies revealed that activation of the ATP-depleting CD39 and CD73 ectonucleotidases is essential for activin-A\u2013induced suppression of the pathogenic signature and the encephalitogenic functions of Th17 cells. Mechanistically, the aryl hydrocarbon receptor, along with STAT3 and c-Maf, are recruited to promoter elements on\n                    <jats:italic>Entpd1<\/jats:italic>\n                    and\n                    <jats:italic>Nt5e<\/jats:italic>\n                    (encoding CD39 and CD73, respectively) and other antiinflammatory genes, and control their expression in Th17 cells in response to activin-A. Notably, we show that activin-A negatively regulates the metabolic sensor, hypoxia-inducible factor-1\u03b1, and key inflammatory proteins linked to pathogenic Th17 cell states. Of translational relevance, we demonstrate that activin-A is induced in the CNS of individuals with MS and restrains human Th17 cell responses. These findings uncover activin-A as a critical controller of Th17 cell pathogenicity that can be targeted for the suppression of autoimmune CNS inflammation.\n                  <\/jats:p>","DOI":"10.1073\/pnas.1918196117","type":"journal-article","created":{"date-parts":[[2020,5,14]],"date-time":"2020-05-14T20:09:30Z","timestamp":1589486970000},"page":"12269-12280","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":39,"title":["Activin-A limits Th17 pathogenicity and autoimmune neuroinflammation via CD39 and CD73 ectonucleotidases and Hif1-\u03b1\u2013dependent pathways"],"prefix":"10.1073","volume":"117","author":[{"given":"Ioannis","family":"Morianos","sequence":"first","affiliation":[{"name":"Cellular Immunology Laboratory, Biomedical Research Foundation of the Academy of Athens, 115 27 Athens, Greece;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2956-2221","authenticated-orcid":false,"given":"Aikaterini I.","family":"Trochoutsou","sequence":"additional","affiliation":[{"name":"Cellular Immunology Laboratory, Biomedical Research Foundation of the Academy of Athens, 115 27 Athens, Greece;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3022-4350","authenticated-orcid":false,"given":"Gina","family":"Papadopoulou","sequence":"additional","affiliation":[{"name":"Cellular Immunology Laboratory, Biomedical Research Foundation of the Academy of Athens, 115 27 Athens, Greece;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Semitekolou","sequence":"additional","affiliation":[{"name":"Cellular Immunology Laboratory, Biomedical Research Foundation of the Academy of Athens, 115 27 Athens, Greece;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5647-6505","authenticated-orcid":false,"given":"Aggelos","family":"Banos","sequence":"additional","affiliation":[{"name":"Division of Immunobiology, Biomedical Research Foundation of the Academy of Athens, 115 27 Athens, Greece;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2142-3021","authenticated-orcid":false,"given":"Dimitris","family":"Konstantopoulos","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology and Genetics, Biomedical Sciences Research Center \u201cAlexander Fleming\u201d, 16672 Athens, Greece;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antigoni","family":"Manousopoulou","sequence":"additional","affiliation":[{"name":"Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Kapasa","sequence":"additional","affiliation":[{"name":"Molecular Biology Laboratory, Biomedical Research Foundation of the Academy of Athens, 115 27 Athens, Greece;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ping","family":"Wei","sequence":"additional","affiliation":[{"name":"Department of Oncology and Medicine, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21231;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brett","family":"Lomenick","sequence":"additional","affiliation":[{"name":"Proteome Exploration Laboratory, Beckman Institute, Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4589-1612","authenticated-orcid":false,"given":"Elise","family":"Belaidi","sequence":"additional","affiliation":[{"name":"Laboratoire HP2, University Grenoble Alpes, F-38042 Grenoble, France;"},{"name":"INSERM, U1042 Grenoble, France;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Themis","family":"Kalamatas","sequence":"additional","affiliation":[{"name":"Department of Neurology, \u201cG. Gennimatas\u201d General State Hospital of Athens, 115 27 Athens, Greece;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Klinta","family":"Karageorgiou","sequence":"additional","affiliation":[{"name":"Department of Neurology, Athens Medical Center, 151 25 Athens, Greece;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Triantafyllos","family":"Doskas","sequence":"additional","affiliation":[{"name":"Department of Neurology, Athens Naval Hospital, 115 21 Athens, Greece;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federica","family":"Sallusto","sequence":"additional","affiliation":[{"name":"Institute of Microbiology, Eidgen\u00f6ssiche Technische Hochschule, 8093 Z\u00fcrich, Switzerland;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fan","family":"Pan","sequence":"additional","affiliation":[{"name":"Department of Oncology and Medicine, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21231;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1050-0805","authenticated-orcid":false,"given":"Spiros D.","family":"Garbis","sequence":"additional","affiliation":[{"name":"Proteome Exploration Laboratory, Beckman Institute, Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francisco J.","family":"Quintana","sequence":"additional","affiliation":[{"name":"Ann Romney Center for Neurologic Diseases, Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, MA 02115;"},{"name":"The Broad Institute of MIT and Harvard, Boston, MA 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7944-2343","authenticated-orcid":false,"given":"Georgina","family":"Xanthou","sequence":"additional","affiliation":[{"name":"Cellular Immunology Laboratory, Biomedical Research Foundation of the Academy of Athens, 115 27 Athens, Greece;"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2020,5,14]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1038\/nri3871","article-title":"Immunopathology of multiple sclerosis","volume":"15","author":"Dendrou C. A.","year":"2015","unstructured":"C. A. Dendrou, L. Fugger, M. A. Friese, Immunopathology of multiple sclerosis. Nat. Rev. Immunol. 15, 545\u2013558 (2015).","journal-title":"Nat. Rev. Immunol."},{"key":"e_1_3_4_2_2","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1038\/nri.2016.144","article-title":"T cell responses in the central nervous system","volume":"17","author":"Korn T.","year":"2017","unstructured":"T. Korn, A. Kallies, T cell responses in the central nervous system. Nat. Rev. Immunol. 17, 179\u2013194 (2017).","journal-title":"Nat. Rev. Immunol."},{"key":"e_1_3_4_3_2","doi-asserted-by":"crossref","first-page":"2211","DOI":"10.1172\/JCI78085","article-title":"Pouring fuel on the fire: Th17 cells, the environment, and autoimmunity","volume":"125","author":"Burkett P. R.","year":"2015","unstructured":"P. R. Burkett, G. Meyer zu Horste, V. K. Kuchroo, Pouring fuel on the fire: Th17 cells, the environment, and autoimmunity. J. Clin. Invest. 125, 2211\u20132219 (2015).","journal-title":"J. Clin. Invest."},{"key":"e_1_3_4_4_2","first-page":"5314541","article-title":"Th17 cells pathways in multiple sclerosis and neuromyelitis optica spectrum disorders: Pathophysiological and therapeutic implications","volume":"2016","author":"Dos Passos G. R.","year":"2016","unstructured":"G. R. Dos Passos, D. K. Sato, J. Becker, K. Fujihara, Th17 cells pathways in multiple sclerosis and neuromyelitis optica spectrum disorders: Pathophysiological and therapeutic implications. Mediators Inflamm. 2016, 5314541 (2016).","journal-title":"Mediators Inflamm."},{"key":"e_1_3_4_5_2","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1177\/135245859900500206","article-title":"Interleukin-17 mRNA expression in blood and CSF mononuclear cells is augmented in multiple sclerosis","volume":"5","author":"Matusevicius D.","year":"1999","unstructured":"D. Matusevicius ., Interleukin-17 mRNA expression in blood and CSF mononuclear cells is augmented in multiple sclerosis. Mult. Scler. 5, 101\u2013104 (1999).","journal-title":"Mult. Scler."},{"key":"e_1_3_4_6_2","doi-asserted-by":"crossref","first-page":"146","DOI":"10.2353\/ajpath.2008.070690","article-title":"Interleukin-17 production in central nervous system-infiltrating T cells and glial cells is associated with active disease in multiple sclerosis","volume":"172","author":"Tzartos J. S.","year":"2008","unstructured":"J. S. Tzartos ., Interleukin-17 production in central nervous system-infiltrating T cells and glial cells is associated with active disease in multiple sclerosis. Am. J. Pathol. 172, 146\u2013155 (2008).","journal-title":"Am. J. Pathol."},{"key":"e_1_3_4_7_2","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1038\/nri.2017.50","article-title":"The dichotomous nature of T helper 17 cells","volume":"17","author":"Stockinger B.","year":"2017","unstructured":"B. Stockinger, S. Omenetti, The dichotomous nature of T helper 17 cells. Nat. Rev. Immunol. 17, 535\u2013544 (2017).","journal-title":"Nat. Rev. Immunol."},{"key":"e_1_3_4_8_2","doi-asserted-by":"crossref","first-page":"991","DOI":"10.1038\/ni.2416","article-title":"Induction and molecular signature of pathogenic TH17 cells","volume":"13","author":"Lee Y.","year":"2012","unstructured":"Y. Lee ., Induction and molecular signature of pathogenic TH17 cells. Nat. Immunol. 13, 991\u2013999 (2012).","journal-title":"Nat. Immunol."},{"key":"e_1_3_4_9_2","doi-asserted-by":"crossref","first-page":"1284","DOI":"10.1016\/j.immuni.2016.05.015","article-title":"The MicroRNA-183-96-182 cluster promotes T helper 17 cell pathogenicity by negatively regulating transcription factor Foxo1 expression","volume":"44","author":"Ichiyama K.","year":"2016","unstructured":"K. Ichiyama ., The MicroRNA-183-96-182 cluster promotes T helper 17 cell pathogenicity by negatively regulating transcription factor Foxo1 expression. Immunity 44, 1284\u20131298 (2016).","journal-title":"Immunity"},{"key":"e_1_3_4_10_2","doi-asserted-by":"crossref","first-page":"1413","DOI":"10.1016\/j.cell.2015.10.068","article-title":"CD5L\/AIM regulates lipid biosynthesis and restrains Th17 cell pathogenicity","volume":"163","author":"Wang C.","year":"2015","unstructured":"C. Wang ., CD5L\/AIM regulates lipid biosynthesis and restrains Th17 cell pathogenicity. Cell 163, 1413\u20131427 (2015).","journal-title":"Cell"},{"key":"e_1_3_4_11_2","doi-asserted-by":"crossref","first-page":"514","DOI":"10.1038\/nature10957","article-title":"Pathogen-induced human TH17 cells produce IFN-\u03b3 or IL-10 and are regulated by IL-1\u03b2","volume":"484","author":"Zielinski C. E.","year":"2012","unstructured":"C. E. Zielinski ., Pathogen-induced human TH17 cells produce IFN-\u03b3 or IL-10 and are regulated by IL-1\u03b2. Nature 484, 514\u2013518 (2012).","journal-title":"Nature"},{"key":"e_1_3_4_12_2","doi-asserted-by":"crossref","first-page":"1600","DOI":"10.1038\/s41467-017-01571-8","article-title":"Transcriptional signature of human pro-inflammatory TH17 cells identifies reduced IL10 gene expression in multiple sclerosis","volume":"8","author":"Hu D.","year":"2017","unstructured":"D. Hu ., Transcriptional signature of human pro-inflammatory TH17 cells identifies reduced IL10 gene expression in multiple sclerosis. Nat. Commun. 8, 1600 (2017).","journal-title":"Nat. Commun."},{"key":"e_1_3_4_13_2","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1038\/nature14452","article-title":"Th17 cells transdifferentiate into regulatory T cells during resolution of inflammation","volume":"523","author":"Gagliani N.","year":"2015","unstructured":"N. Gagliani ., Th17 cells transdifferentiate into regulatory T cells during resolution of inflammation. Nature 523, 221\u2013225 (2015).","journal-title":"Nature"},{"key":"e_1_3_4_14_2","doi-asserted-by":"crossref","first-page":"3770","DOI":"10.1038\/ncomms4770","article-title":"IL-27 and IL-12 oppose pro-inflammatory IL-23 in CD4+ T cells by inducing Blimp1","volume":"5","author":"Heinemann C.","year":"2014","unstructured":"C. Heinemann ., IL-27 and IL-12 oppose pro-inflammatory IL-23 in CD4+ T cells by inducing Blimp1. Nat. Commun. 5, 3770 (2014).","journal-title":"Nat. Commun."},{"key":"e_1_3_4_15_2","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1016\/j.cytogfr.2013.03.003","article-title":"The activins and their binding protein, follistatin-Diagnostic and therapeutic targets in inflammatory disease and fibrosis","volume":"24","author":"Hedger M. P.","year":"2013","unstructured":"M. P. Hedger, D. M. de Kretser, The activins and their binding protein, follistatin-Diagnostic and therapeutic targets in inflammatory disease and fibrosis. Cytokine Growth Factor Rev. 24, 285\u2013295 (2013).","journal-title":"Cytokine Growth Factor Rev."},{"key":"e_1_3_4_16_2","doi-asserted-by":"crossref","first-page":"723","DOI":"10.1038\/nri.2016.112","article-title":"Immunoregulation by members of the TGF\u03b2 superfamily","volume":"16","author":"Chen W.","year":"2016","unstructured":"W. Chen, P. Ten Dijke, Immunoregulation by members of the TGF\u03b2 superfamily. Nat. Rev. Immunol. 16, 723\u2013740 (2016).","journal-title":"Nat. Rev. Immunol."},{"key":"e_1_3_4_17_2","doi-asserted-by":"crossref","first-page":"1000","DOI":"10.1016\/j.jaci.2011.12.965","article-title":"Activin A and TGF-\u03b2 promote T(H)9 cell-mediated pulmonary allergic pathology","volume":"129","author":"Jones C. P.","year":"2012","unstructured":"C. P. Jones ., Activin A and TGF-\u03b2 promote T(H)9 cell-mediated pulmonary allergic pathology. J. Allergy Clin. Immunol. 129, 1000\u201310.e3 (2012).","journal-title":"J. Allergy Clin. Immunol."},{"key":"e_1_3_4_18_2","doi-asserted-by":"crossref","first-page":"102314","DOI":"10.1016\/j.jaut.2019.102314","article-title":"Activin-A in the regulation of immunity in health and disease","volume":"104","author":"Morianos I.","year":"2019","unstructured":"I. Morianos, G. Papadopoulou, M. Semitekolou, G. Xanthou, Activin-A in the regulation of immunity in health and disease. J. Autoimmun. 104, 102314 (2019).","journal-title":"J. Autoimmun."},{"key":"e_1_3_4_19_2","doi-asserted-by":"crossref","first-page":"4633","DOI":"10.4049\/jimmunol.0803143","article-title":"Activin a promotes the TGF-\u03b2-induced conversion of CD4+CD25- T cells into Foxp3+ induced regulatory T cells","volume":"182","author":"Huber S.","year":"2009","unstructured":"S. Huber ., Activin a promotes the TGF-\u03b2-induced conversion of CD4+CD25- T cells into Foxp3+ induced regulatory T cells. J. Immunol. 182, 4633\u20134640 (2009).","journal-title":"J. Immunol."},{"key":"e_1_3_4_20_2","doi-asserted-by":"crossref","first-page":"976","DOI":"10.1038\/ni.3494","article-title":"Activin A programs the differentiation of human TFH cells","volume":"17","author":"Locci M.","year":"2016","unstructured":"M. Locci ., Activin A programs the differentiation of human TFH cells. Nat. Immunol. 17, 976\u2013984 (2016).","journal-title":"Nat. Immunol."},{"key":"e_1_3_4_21_2","doi-asserted-by":"crossref","first-page":"1769","DOI":"10.1084\/jem.20082603","article-title":"Activin-A induces regulatory T cells that suppress T helper cell immune responses and protect from allergic airway disease","volume":"206","author":"Semitekolou M.","year":"2009","unstructured":"M. Semitekolou ., Activin-A induces regulatory T cells that suppress T helper cell immune responses and protect from allergic airway disease. J. Exp. Med. 206, 1769\u20131785 (2009).","journal-title":"J. Exp. Med."},{"key":"e_1_3_4_22_2","doi-asserted-by":"crossref","first-page":"E2891","DOI":"10.1073\/pnas.1616942114","article-title":"Activin-A co-opts IRF4 and AhR signaling to induce human regulatory T cells that restrain asthmatic responses","volume":"114","author":"Tousa S.","year":"2017","unstructured":"S. Tousa ., Activin-A co-opts IRF4 and AhR signaling to induce human regulatory T cells that restrain asthmatic responses. Proc. Natl. Acad. Sci. U.S.A. 114, E2891\u2013E2900 (2017).","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"e_1_3_4_23_2","doi-asserted-by":"crossref","first-page":"1327","DOI":"10.1038\/nm.3704","article-title":"De novo fatty acid synthesis controls the fate between regulatory T and T helper 17 cells","volume":"20","author":"Berod L.","year":"2014","unstructured":"L. Berod ., De novo fatty acid synthesis controls the fate between regulatory T and T helper 17 cells. Nat. Med. 20, 1327\u20131333 (2014).","journal-title":"Nat. Med."},{"key":"e_1_3_4_24_2","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1038\/s41586-018-0806-7","article-title":"Metabolic heterogeneity underlies reciprocal fates of TH17 cell stemness and plasticity","volume":"565","author":"Karmaus P. W. F.","year":"2019","unstructured":"P. W. F. Karmaus ., Metabolic heterogeneity underlies reciprocal fates of TH17 cell stemness and plasticity. Nature 565, 101\u2013105 (2019).","journal-title":"Nature"},{"key":"e_1_3_4_25_2","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1038\/nature06880","article-title":"Control of T(reg) and T(H)17 cell differentiation by the aryl hydrocarbon receptor","volume":"453","author":"Quintana F. J.","year":"2008","unstructured":"F. J. Quintana ., Control of T(reg) and T(H)17 cell differentiation by the aryl hydrocarbon receptor. Nature 453, 65\u201371 (2008).","journal-title":"Nature"},{"key":"e_1_3_4_26_2","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1038\/ni.1993","article-title":"Fate mapping of IL-17-producing T cells in inflammatory responses","volume":"12","author":"Hirota K.","year":"2011","unstructured":"K. Hirota ., Fate mapping of IL-17-producing T cells in inflammatory responses. Nat. Immunol. 12, 255\u2013263 (2011).","journal-title":"Nat. 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