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dc.contributor.authorSchmidt, Angelika
dc.contributor.authorMarabita, Francesco
dc.contributor.authorKiani, Narsis A.
dc.contributor.authorGross, Catharina C.
dc.contributor.authorJohansson, Henrik J.
dc.contributor.authorÉliás, Szabolcs
dc.contributor.authorRautio, Sini
dc.contributor.authorEriksson, Matilda
dc.contributor.authorFernandes, Sunjay Jude
dc.contributor.authorSilberberg, Gilad
dc.contributor.authorUllah, Ubaid
dc.contributor.authorBhatia, Urvashi
dc.contributor.authorLähdesmäki, Harri
dc.contributor.authorLehtiö, Janne
dc.contributor.authorGomez-Cabrero, David
dc.contributor.authorWiendl, Heinz
dc.contributor.authorLahesmaa, Riitta
dc.contributor.authorTegner, Jesper
dc.date.accessioned2018-05-10T08:56:43Z
dc.date.available2018-05-10T08:56:43Z
dc.date.issued2018-05-07
dc.identifier.citationSchmidt A, Marabita F, Kiani NA, Gross CC, Johansson HJ, et al. (2018) Time-resolved transcriptome and proteome landscape of human regulatory T cell (Treg) differentiation reveals novel regulators of FOXP3. BMC Biology 16. Available: http://dx.doi.org/10.1186/s12915-018-0518-3.
dc.identifier.issn1741-7007
dc.identifier.pmid29730990
dc.identifier.doi10.1186/s12915-018-0518-3
dc.identifier.urihttp://hdl.handle.net/10754/627826
dc.description.abstractBackgroundRegulatory T cells (Tregs) expressing the transcription factor FOXP3 are crucial mediators of self-tolerance, preventing autoimmune diseases but possibly hampering tumor rejection. Clinical manipulation of Tregs is of great interest, and first-in-man trials of Treg transfer have achieved promising outcomes. Yet, the mechanisms governing induced Treg (iTreg) differentiation and the regulation of FOXP3 are incompletely understood.ResultsTo gain a comprehensive and unbiased molecular understanding of FOXP3 induction, we performed time-series RNA sequencing (RNA-Seq) and proteomics profiling on the same samples during human iTreg differentiation. To enable the broad analysis of universal FOXP3-inducing pathways, we used five differentiation protocols in parallel. Integrative analysis of the transcriptome and proteome confirmed involvement of specific molecular processes, as well as overlap of a novel iTreg subnetwork with known Treg regulators and autoimmunity-associated genes. Importantly, we propose 37 novel molecules putatively involved in iTreg differentiation. Their relevance was validated by a targeted shRNA screen confirming a functional role in FOXP3 induction, discriminant analyses classifying iTregs accordingly, and comparable expression in an independent novel iTreg RNA-Seq dataset.ConclusionThe data generated by this novel approach facilitates understanding of the molecular mechanisms underlying iTreg generation as well as of the concomitant changes in the transcriptome and proteome. Our results provide a reference map exploitable for future discovery of markers and drug candidates governing control of Tregs, which has important implications for the treatment of cancer, autoimmune, and inflammatory diseases.
dc.description.sponsorshipAS was supported by a Marie Curie Intra European Fellowship within the 7th European Community Framework Programme (FP7, Project ID: 326930, project acronym ‘ITREGDIFFERENTIATION’), the Dr. Åke Olsson Foundation, Karolinska Institutet Stiftelser & Fonder, the Erik and Edith Fernström Foundation, the German Society for Immunology, and EUROIMMUN AG. AS and JT were supported by a CERIC (Center of Excellence for Research on Inflammation and Cardiovascular disease) grant. AS, JT, and DGC received funding from the European Research Council under the European Union’s Seventh Framework Programme (FP7, ERC Project ID: 617393 ‘CAUSALPATH’). JT was supported by Vetenskapsrådet Medicine and Health (Dnr 2011–3264), Torsten Söderberg Foundation, FP7 STATegra, AFA Insurance, and Stockholm County Council. FM was supported by the Karolinska Institutet Stiftelser & Fonder. NAK was supported by Vinnova VINNMER fellowship, Stratneuro and Karolinska Institutet Stiftelser & Fonder. SE was supported by Karolinska Institute’s faculty funds for doctoral education (KID-funding). HW and CCG received funding from the German Research Foundation (DFG, Collaborative Research Centre CRC 128 ‘Initiating/Effector versus Regulatory Mechanisms in Multiple Sclerosis – Progress towards Tackling the Disease’ project A09 to HW and CCG and Z02 to HW) and from the Federal Ministry of Education and Research (BMBF) supporting the Disease-related Competence Network for Multiple Sclerosis (Krankheitsbezogenes Netzwerk Multiple Sklerose, KKNMS, FKZ 01FI1603a). UB was supported by the Cluster of Excellence ‘Cells in Motion’ (CiM) Bridging Fund. RL, HL, and HW were supported by the Academy of Finland (AoF; grant 256355) and the German Research Foundation (DFG) (Immunology Initiative ‘Systems biology approach to molecular mechanisms of human TGFb induced iTreg cell differentiation and the role of iTreg in Multiple sclerosis’). RL and HL were supported by the AoF Centre of Excellence in Molecular Systems Immunology and Physiology Research 2012–2017 (AoF grant 250114). RL was supported by AoF grant 294337, the Sigrid Juselius Foundation and the Paulo Foundation.
dc.publisherSpringer Nature
dc.relation.urlhttps://bmcbiol.biomedcentral.com/articles/10.1186/s12915-018-0518-3
dc.rightsThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectRegulatory T cells
dc.subjectTreg
dc.subjectiTreg
dc.subjectFOXP3
dc.subjectT cell differentiation
dc.subjectRNA sequencing (RNA-Seq)
dc.subjectProteomics
dc.subjectData integration
dc.subjectTGF-β
dc.titleTime-resolved transcriptome and proteome landscape of human regulatory T cell (Treg) differentiation reveals novel regulators of FOXP3
dc.typeArticle
dc.contributor.departmentBiological and Environmental Sciences and Engineering (BESE) Division
dc.contributor.departmentBioscience Program
dc.contributor.departmentComputer, Electrical and Mathematical Sciences and Engineering (CEMSE) Division
dc.identifier.journalBMC Biology
dc.eprint.versionPublisher's Version/PDF
dc.contributor.institutionDepartment of Signaling and Gene Expression, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA.
dc.contributor.institutionUnit of Computational Medicine, Center for Molecular Medicine, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital and Science for Life Laboratory, 17176 Stockholm, Sweden.
dc.contributor.institutionNeuroimmunology Unit, Center for Molecular Medicine, Department of Clinical Neuroscience, Karolinska Institutet & Karolinska University Hospital, 17176 Stockholm, Sweden.
dc.contributor.institutionDepartment of Neurology, University Hospital Münster and University of Münster, 48149 Münster, Germany.
dc.contributor.institutionDepartment Oncology-Pathology, Cancer Proteomics Mass Spectrometry, Science for Life Laboratory, Karolinska Institutet, 17176 Stockholm, Sweden.
dc.contributor.institutionDepartment of Computer Science, Aalto University, FI-00076 Aalto, Finland.
dc.contributor.institutionTurku Centre for Biotechnology, University of Turku and Åbo Akademi University, FI-20521 Turku, Finland.
dc.contributor.institutionMucosal and Salivary Biology Division, King’s College London Dental Institute, London SE1 9RT, UK.
kaust.personTegner, Jesper
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refterms.dateFOA2018-06-13T11:00:07Z
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dc.date.published-online2018-05-07
dc.date.published-print2018-12


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This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Except where otherwise noted, this item's license is described as This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.