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2018 ; 16
(1
): 47
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Time-resolved transcriptome and proteome landscape of human regulatory T cell
(Treg) differentiation reveals novel regulators of FOXP3
#MMPMID29730990
Schmidt A
; Marabita F
; Kiani NA
; Gross CC
; Johansson HJ
; Éliás S
; Rautio S
; Eriksson M
; Fernandes SJ
; Silberberg G
; Ullah U
; Bhatia U
; Lähdesmäki H
; Lehtiö J
; Gomez-Cabrero D
; Wiendl H
; Lahesmaa R
; Tegnér J
BMC Biol
2018[May]; 16
(1
): 47
PMID29730990
show ga
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.