{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,5]],"date-time":"2025-11-05T14:29:55Z","timestamp":1762352995449,"version":"3.41.2"},"reference-count":55,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2020,12,4]],"date-time":"2020-12-04T00:00:00Z","timestamp":1607040000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001711","name":"Schweizerischer Nationalfonds zur F\u00f6rderung der Wissenschaftlichen Forschung","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001711","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>IFN-\u03b2 treatment is a commonly used therapy for relapsing-remitting multiple sclerosis (MS), while vitamin D deficiency correlates with an increased risk of MS and\/or its activity. MS is a demyelinating chronic inflammatory disease of the central nervous system, in which activated T lymphocytes play a major role, and may represent direct targets of IFN-\u03b2 and vitamin D activities. However, the underlying mechanism of action of vitamin D and IFN-\u03b2, alone or in combination, remains incompletely understood, especially when considering their direct effects on the ability of T lymphocytes to produce inflammatory cytokines. We profiled the expression of immune-related genes and microRNAs in primary human T lymphocytes in response to vitamin D and IFN-\u03b2, and we dissected the impact of these treatments on cytokine production and T cell proliferation. We found that the treatments influenced primarily memory T cell plasticity, rather than polarization toward a stable phenotype. Moreover, our data revealed extensive reprogramming of the transcriptional output of primary T cells in response to vitamin D and IFN-\u03b2 and provide the bases for further mechanistic insights into these commonly used treatments.<\/jats:p>","DOI":"10.3389\/fimmu.2020.566781","type":"journal-article","created":{"date-parts":[[2020,12,4]],"date-time":"2020-12-04T04:57:09Z","timestamp":1607057829000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":10,"title":["Vitamin D and IFN-\u03b2 Modulate the Inflammatory Gene Expression Program of Primary Human T Lymphocytes"],"prefix":"10.3389","volume":"11","author":[{"given":"Niccol\u00f2","family":"Bianchi","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stefan","family":"Emming","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chiara","family":"Zecca","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Silvia","family":"Monticelli","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2020,12,4]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20190460","article-title":"Pathogenic T cell cytokines in multiple sclerosis","volume":"217","author":"Wagner","year":"2020","journal-title":"J Exp Med"},{"key":"B2","doi-asserted-by":"crossref","DOI":"10.4049\/jimmunol.161.7.3639","article-title":"Protection from collagen-induced arthritis in granulocyte-macrophage colony-stimulating factor-deficient mice","volume":"161","author":"Campbell","year":"1998","journal-title":"J Immunol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1038\/ni.2027","article-title":"RORgammat drives production of the cytokine GM-CSF in helper T cells, which is essential for the effector phase of autoimmune neuroinflammation","volume":"12","author":"Codarri","year":"2011","journal-title":"Nat Immunol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1084\/jem.194.7.873","article-title":"Granulocyte macrophage colony-stimulating factor: a new putative therapeutic target in multiple sclerosis","volume":"194","author":"McQualter","year":"2001","journal-title":"J Exp Med"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20071119","article-title":"GM-CSF mediates autoimmunity by enhancing IL-6-dependent Th17 cell development and survival","volume":"205","author":"Sonderegger","year":"2008","journal-title":"J Exp Med"},{"key":"B6","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1038\/nri.2016.123","article-title":"Cytokine networks in neuroinflammation","volume":"17","author":"Becher","year":"2017","journal-title":"Nat Rev Immunol"},{"key":"B7","doi-asserted-by":"publisher","first-page":"499","DOI":"10.1002\/ana.21652","article-title":"T-helper 17 cells expand in multiple sclerosis and are inhibited by interferon-beta","volume":"65","author":"Durelli","year":"2009","journal-title":"Ann Neurol"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1302580","article-title":"The role of endogenous IFN-beta in the regulation of Th17 responses in patients with relapsing-remitting multiple sclerosis","volume":"192","author":"Tao","year":"2014","journal-title":"J Immunol"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.0803227","article-title":"IFN-beta inhibits human Th17 cell differentiation","volume":"183","author":"Ramgolam","year":"2009","journal-title":"J Immunol"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbi.2011.03.007","article-title":"IL-27 mediates the response to IFN-beta therapy in multiple sclerosis patients by inhibiting Th17 cells","volume":"25","author":"Sweeney","year":"2011","journal-title":"Brain Behav Immun"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1403243","article-title":"Expression of GM-CSF in T Cells Is Increased in Multiple Sclerosis and Suppressed by IFN-beta Therapy","volume":"194","author":"Rasouli","year":"2015","journal-title":"J Immunol"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2008.03.011","article-title":"Distinct and nonredundant in vivo functions of IFNAR on myeloid cells limit autoimmunity in the central nervous system","volume":"28","author":"Prinz","year":"2008","journal-title":"Immunity"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.170.9.4776","article-title":"IFN-beta gene deletion leads to augmented and chronic demyelinating experimental autoimmune encephalomyelitis","volume":"170","author":"Teige","year":"2003","journal-title":"J Immunol"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1500036","article-title":"IFN-alpha\/beta receptor signaling promotes regulatory T cell development and function under stress conditions","volume":"194","author":"Metidji","year":"2015","journal-title":"J Immunol"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1189\/jlb.3A1214-598R","article-title":"IFNAR signaling directly modulates T lymphocyte activity, resulting in milder experimental autoimmune encephalomyelitis development","volume":"99","author":"Kavrochorianou","year":"2016","journal-title":"J Leukoc Biol"},{"key":"B16","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1007\/s40120-017-0086-4","article-title":"and Multiple Sclerosis: A Comprehensive Review","volume":"7","author":"Sintzel","year":"2018","journal-title":"Neurol Ther"},{"key":"B17","doi-asserted-by":"publisher","first-page":"36","DOI":"10.1016\/j.jneuroim.2015.02.007","article-title":"GM-CSF production by CD4+ T cells in MS patients: regulation by regulatory T cells and vitamin D","volume":"280","author":"Peelen","year":"2015","journal-title":"J Neuroimmunol"},{"key":"B18","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1016\/j.jneuroim.2016.08.005","article-title":"Vitamin D modulates different IL-17-secreting T cell subsets in multiple sclerosis patients","volume":"299","author":"da Costa","year":"2016","journal-title":"J Neuroimmunol"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.0803217","article-title":"1,25-Dihydroxyvitamin D3 and IL-2 combine to inhibit T cell production of inflammatory cytokines and promote development of regulatory T cells expressing CTLA-4 and FoxP3","volume":"183","author":"Jeffery","year":"2009","journal-title":"J Immunol"},{"key":"B20","doi-asserted-by":"crossref","DOI":"10.4049\/jimmunol.134.5.3032","article-title":"1,25-Dihydroxyvitamin D3 suppresses human T helper\/inducer lymphocyte activity in vitro","volume":"134","author":"Lemire","year":"1985","journal-title":"J Immunol"},{"key":"B21","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1016\/j.jneuroim.2016.09.018","article-title":"Immune regulatory effects of high dose vitamin D3 supplementation in a randomized controlled trial in relapsing remitting multiple sclerosis patients receiving IFNbeta; the SOLARIUM study","volume":"300","author":"Muris","year":"2016","journal-title":"J Neuroimmunol"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1212\/NXI.0000000000000597","article-title":"Cholecalciferol in relapsing-remitting MS: A randomized clinical trial (CHOLINE)","volume":"6","author":"Camu","year":"2019","journal-title":"Neurol Neuroimmunol Neuroinflamm"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000008445","article-title":"Randomized trial of daily high-dose vitamin D3 in patients with RRMS receiving subcutaneous interferon beta-1a","volume":"93","author":"Hupperts","year":"2019","journal-title":"Neurology"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0b013e31825fded9","article-title":"Interferon-beta and serum 25-hydroxyvitamin D interact to modulate relapse risk in MS","volume":"79","author":"Stewart","year":"2012","journal-title":"Neurology"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1016\/j.jneuroim.2015.02.001","article-title":"Vitamin D status and effect of interferon-beta1a treatment on MRI activity and serum inflammation markers in relapsing-remitting multiple sclerosis","volume":"280","author":"Rosjo","year":"2015","journal-title":"J\u00a0Neuroimmunol"},{"key":"B26","doi-asserted-by":"publisher","first-page":"78","DOI":"10.1038\/ni872","article-title":"Memory and flexibility of cytokine gene expression as separable properties of human T(H)1 and T(H)2 lymphocytes","volume":"4","author":"Messi","year":"2003","journal-title":"Nat Immunol"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1101\/gr.107920.110","article-title":"A ChIP-seq defined genome-wide map of vitamin D receptor binding: associations with disease and evolution","volume":"20","author":"Ramagopalan","year":"2010","journal-title":"Genome Res"},{"key":"B28","doi-asserted-by":"publisher","first-page":"41","DOI":"10.4137\/GRSB.S11433","article-title":"A Comprehensive Profile of ChIP-Seq-Based STAT1 Target Genes Suggests the Complexity of STAT1-Mediated Gene Regulatory Mechanisms","volume":"7","author":"Satoh","year":"2013","journal-title":"Gene Regul Syst Bio"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.4161\/jkst.23060","article-title":"STAT heterodimers in immunity: A mixed message or a unique signal","volume":"2","author":"Delgoffe","year":"2013","journal-title":"JAKSTAT"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1101\/2020.02.28.969634","article-title":"Vitamin D receptor and STAT3 cooperate to establish TET2-mediated tolerogenesis","author":"Catal\u00e0-Moll","year":"2020","journal-title":"bioRxiv"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1016\/j.smim.2013.10.015","article-title":"MicroRNAs in T helper cell differentiation and plasticity","volume":"25","author":"Monticelli","year":"2013","journal-title":"Semin Immunol"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2010.09.009","article-title":"MicroRNA-155 promotes autoimmune inflammation by enhancing inflammatory T cell development","volume":"33","author":"O\u2019Connell","year":"2010","journal-title":"Immunity"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2011.07.009","article-title":"MicroRNA-29 regulates T-box transcription factors and interferon-gamma production in helper T cells","volume":"35","author":"Steiner","year":"2011","journal-title":"Immunity"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20150990","article-title":"miR-23~27~24 clusters control effector T cell differentiation and function","volume":"213","author":"Cho","year":"2016","journal-title":"J Exp Med"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20112218","article-title":"miR-146a controls the resolution of T cell responses in mice","volume":"209","author":"Yang","year":"2012","journal-title":"J Exp Med"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1093\/carcin\/bgv152","article-title":"miR-342-3p regulates MYC transcriptional activity via direct repression of E2F1 in human lung cancer","volume":"36","author":"Tai","year":"2015","journal-title":"Carcinogenesis"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M116.733733","article-title":"miR-30 Family Controls Proliferation and Differentiation of Intestinal Epithelial Cell Models by Directing a Broad Gene Expression Program That Includes SOX9 and the Ubiquitin Ligase Pathway","volume":"291","author":"Peck","year":"2016","journal-title":"J Biol Chem"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2017.08.060","article-title":"miR-150 Regulates Memory CD8 T Cell Differentiation via c-Myb","volume":"20","author":"Chen","year":"2017","journal-title":"Cell Rep"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-07-2538","article-title":"The promyelocytic leukemia zinc finger-microRNA-221\/-222 pathway controls melanoma progression through multiple oncogenic mechanisms","volume":"68","author":"Felicetti","year":"2008","journal-title":"Cancer Res"},{"key":"B40","doi-asserted-by":"publisher","first-page":"78","DOI":"10.1016\/j.immuni.2016.12.017","article-title":"Effector Regulatory T Cell Differentiation and Immune Homeostasis Depend on the Transcription Factor Myb","volume":"46","author":"Dias","year":"2017","journal-title":"Immunity"},{"key":"B41","doi-asserted-by":"publisher","first-page":"36","DOI":"10.1038\/nri3581","article-title":"Regulation of type I interferon responses","volume":"14","author":"Ivashkiv","year":"2014","journal-title":"Nat Rev Immunol"},{"key":"B42","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1016\/j.cellimm.2011.02.008","article-title":"IRF4 regulates IL-10 gene expression in CD4(+) T cells through differential nuclear translocation","volume":"268","author":"Lee","year":"2011","journal-title":"Cell Immunol"},{"key":"B43","doi-asserted-by":"publisher","first-page":"593","DOI":"10.1038\/ni.2576","article-title":"The microRNA miR-155 controls CD8(+) T cell responses by regulating interferon signaling","volume":"14","author":"Gracias","year":"2013","journal-title":"Nat Immunol"},{"key":"B44","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1016\/j.cell.2004.12.035","article-title":"Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets","volume":"120","author":"Lewis","year":"2005","journal-title":"Cell"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-065X.2010.00923.x","article-title":"The PD-1 pathway in tolerance and autoimmunity","volume":"236","author":"Francisco","year":"2010","journal-title":"Immunol Rev"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1016\/j.jneuroim.2006.10.006","article-title":"PD-1\/PD-L1, but not PD-1\/PD-L2, interactions regulate the severity of experimental autoimmune encephalomyelitis","volume":"182","author":"Carter","year":"2007","journal-title":"J Neuroimmunol"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2020.07.002","article-title":"Anti-inflammatory Roles of Glucocorticoids Are Mediated by Foxp3(+) Regulatory T Cells via a miR-342-Dependent Mechanism","volume":"53","author":"Kim","year":"2020","journal-title":"Immunity"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1002\/eji.201040632","article-title":"1,25-Dihydroxyvitamin D3 acts directly on the T lymphocyte vitamin D receptor to inhibit experimental autoimmune encephalomyelitis","volume":"41","author":"Mayne","year":"2011","journal-title":"Eur J Immunol"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-020-0622-8","article-title":"A molecular network regulating the proinflammatory phenotype of human memory T lymphocytes","volume":"21","author":"Emming","year":"2020","journal-title":"Nat Immunol"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.0802226","article-title":"IFN-beta1a inhibits the secretion of Th17-polarizing cytokines in human dendritic cells via TLR7 up-regulation","volume":"182","author":"Zhang","year":"2009","journal-title":"J Immunol"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2567.2011.03412.x","article-title":"Regulation of effector and memory T-cell functions by type I interferon","volume":"132","author":"Huber","year":"2011","journal-title":"Immunology"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2016.00697","article-title":"Vitamin D in Autoimmunity: Molecular Mechanisms and Therapeutic Potential","volume":"7","author":"Dankers","year":"2016","journal-title":"Front Immunol"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1111\/imm.13124","article-title":"Biological and clinical significance of T helper 17 cell plasticity","volume":"158","author":"Mazzoni","year":"2019","journal-title":"Immunology"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0802218105","article-title":"IL-6 blockade inhibits the induction of myelin antigen-specific Th17 cells and Th1 cells in experimental autoimmune encephalomyelitis","volume":"105","author":"Serada","year":"2008","journal-title":"Proc Natl Acad Sci USA"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0809850105","article-title":"IL-6 controls Th17 immunity in vivo by inhibiting the conversion of conventional T cells into Foxp3+ regulatory T cells","volume":"105","author":"Korn","year":"2008","journal-title":"Proc Natl Acad Sci USA"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2020.566781\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,14]],"date-time":"2023-10-14T15:27:25Z","timestamp":1697297245000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2020.566781\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,12,4]]},"references-count":55,"alternative-id":["10.3389\/fimmu.2020.566781"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2020.566781","relation":{},"ISSN":["1664-3224"],"issn-type":[{"type":"electronic","value":"1664-3224"}],"subject":[],"published":{"date-parts":[[2020,12,4]]},"article-number":"566781"}}