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 Tegnér

*Corresponding author for this work

Research output: Contribution to journalArticleScientificpeer-review

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Abstract

Background: Regulatory 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. Results: To 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. Conclusion: The 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
Article number47
Pages (from-to)1-35
JournalBMC Biology
Volume16
Issue number1
DOIs
Publication statusPublished - 7 May 2018
MoE publication typeA1 Journal article-refereed

Keywords

  • Data integration
  • FOXP3
  • ITreg
  • Proteomics
  • Regulatory T cells
  • RNA sequencing (RNA-Seq)
  • T cell differentiation
  • TGF-β
  • Treg

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    Schmidt, A., Marabita, F., Kiani, N. A., Gross, C. C., Johansson, H. J., Éliás, S., Rautio, S., Eriksson, M., Fernandes, S. J., Silberberg, G., Ullah, U., Bhatia, U., Lähdesmäki, H., Lehtiö, J., Gomez-Cabrero, D., Wiendl, H., Lahesmaa, R., & Tegnér, J. (2018). Time-resolved transcriptome and proteome landscape of human regulatory T cell (Treg) differentiation reveals novel regulators of FOXP3. BMC Biology, 16(1), 1-35. [47]. https://doi.org/10.1186/s12915-018-0518-3