Time-resolved transcriptome and proteome landscape of human regulatory T cell (Treg) differentiation reveals novel regulators of FOXP3

Angelika Schmidt, Francesco Marabita, Narsis A. Kiani, Catharina C. Gross, Henrik J. Johansson, Szabolcs Éliás, Sini Rautio, Matilda Eriksson, Sunjay Jude Fernandes, Gilad Silberberg, Ubaid Ullah, Urvashi Bhatia, Harri Lähdesmäki, Janne Lehtiö, David Gomez-Cabrero, Heinz Wiendl, Riitta Lahesmaa, Jesper Tegner

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Abstract

BackgroundRegulatory 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.
Original languageEnglish (US)
JournalBMC Biology
Volume16
Issue number1
DOIs
StatePublished - May 7 2018

Bibliographical note

KAUST Repository Item: Exported on 2020-10-01
Acknowledgements: AS 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.

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  • Time-resolved transcriptome and proteome landscape of human regulatory T cell (Treg) differentiation reveals novel regulators of FOXP3

    Schmidt, A. (Creator), Marabita, F. (Creator), Kiani, N. A. (Creator), Gross, C. C. (Creator), Johansson, H. J. (Creator), Éliás, S. (Creator), Rautio, S. (Creator), Eriksson, M. (Creator), Fernandes, S. J. (Creator), Silberberg, G. (Creator), Ullah, U. (Creator), Bhatia, U. (Creator), Lähdesmäki, H. (Creator), Lehtiö, J. (Creator), Gomez-Cabrero, D. (Creator), Wiendl, H. (Creator), Lahesmaa, R. (Creator), Tegner, J. (Creator), Schmidt, A. (Creator), Marabita, F. (Creator), Kiani, N. A. (Creator), Gross, C. C. (Creator), Johansson, H. J. (Creator), Éliás, S. (Creator), Rautio, S. (Creator), Eriksson, M. (Creator), Fernandes, S. J. (Creator), Silberberg, G. (Creator), Ullah, U. (Creator), Bhatia, U. (Creator), Lähdesmäki, H. (Creator), Lehtiö, J. (Creator), Gomez-Cabrero, D. (Creator), Wiendl, H. (Creator) & Lahesmaa, R. (Creator), figshare, 2018

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