Journal
BMC BIOLOGY
Volume 16, Issue -, Pages -Publisher
BMC
DOI: 10.1186/s12915-018-0518-3
Keywords
Regulatory T cells; Treg; iTreg; FOXP3; T cell differentiation; RNA sequencing (RNA-Seq); Proteomics; Data integration; TGF-beta
Categories
Funding
- Marie Curie Intra European Fellowship within the 7th European Community Framework Programme (FP7) [326930]
- Dr. Ake Olsson Foundation
- Karolinska Institutet Stiftelser Fonder
- Erik and Edith Femstrom Foundation
- German Society for Immunology
- EUROIMMUN AG
- CERIC (Center of Excellence for Research on Inflammation and Cardiovascular disease) grant
- European Research Council under the European Union (ERC) [617393]
- Vetenskapsradet Medicine and Health [2011-3264]
- Torsten Soderberg Foundation
- FP7 STATegra
- AFA Insurance
- Stockholm County Council
- Vinnova VINNMER fellowship
- Stratneuro
- Karolinska Institute's faculty funds
- German Research Foundation (DFG, Collaborative Research Centre) [CRC 128]
- Federal Ministry of Education and Research (BMBF) [FKZ 01FI1603a]
- Cluster of Excellence 'Cells in Motion' (CiM) Bridging Fund
- Academy of Finland (AoF) [256355]
- German Research Foundation (DFG)
- AoF Centre of Excellence in Molecular Systems Immunology and Physiology Research (AoF) [250114]
- AoF [294337]
- Sigrid Juselius Foundation
- Paulo Foundation
- Academy of Finland (AKA) [256355, 256355] Funding Source: Academy of Finland (AKA)
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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.
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