miR-155 inhibition sensitizes CD4+ Th cells for TREG mediated suppression.
BACKGROUND
In humans and mice naturally occurring CD4(+)CD25(+) regulatory T cells (nTregs) are a thymus-derived subset of T cells, crucial for the maintenance of peripheral tolerance by controlling not only potentially autoreactive T cells but virtually all cells of the adaptive and innate immune system. Recent work using Dicer-deficient mice irrevocably demonstrated the importance of miRNAs for nTreg cell-mediated tolerance.


RESULTS
DNA-Microarray analyses of human as well as murine conventional CD4(+) Th cells and nTregs revealed a strong up-regulation of mature miR-155 (microRNA-155) upon activation in both populations. Studying miR-155 expression in FoxP3-deficient scurfy mice and performing FoxP3 ChIP-Seq experiments using activated human T lymphocytes, we show that the expression and maturation of miR-155 seem to be not necessarily regulated by FoxP3. In order to address the functional relevance of elevated miR-155 levels, we transfected miR-155 inhibitors or mature miR-155 RNAs into freshly-isolated human and mouse primary CD4(+) Th cells and nTregs and investigated the resulting phenotype in nTreg suppression assays. Whereas miR-155 inhibition in conventional CD4(+) Th cells strengthened nTreg cell-mediated suppression, overexpression of mature miR-155 rendered these cells unresponsive to nTreg cell-mediated suppression.


CONCLUSIONS
Investigation of FoxP3 downstream targets, certainly of bound and regulated miRNAs revealed the associated function between the master regulator FoxP3 and miRNAs as regulators itself. miR-155 is shown to be crucially involved in nTreg cell mediated tolerance by regulating the susceptibility of conventional human as well as murine CD4(+) Th cells to nTreg cell-mediated suppression.
Boehringer Ingelheim Pharma GmbH & Co. KG, Respiratory Diseases Research, Genomics Group, Biberach an der Riss, Germany.
Heiko F
HF
Stahl
Tanja
T
Fauti
Nina
N
Ullrich
Tobias
T
Bopp
Jan
J
Kubach
Werner
W
Rust
Paul
P
Labhart
Vassili
V
Alexiadis
Christian
C
Becker
Mathias
M
Hafner
Andreas
A
Weith
Martin C
MC
Lenter
Helmut
H
Jonuleit
Edgar
E
Schmitt
Detlev
D
Mennerich
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006801:Humans; D007108:Immune Tolerance; D007113:Immunity, Innate; D053645:Interleukin-2 Receptor alpha Subunit / Q000096:biosynthesis; D007700:Kinetics; D051379:Mice; D035683:MicroRNAs / Q000378:metabolism*; D008954:Models, Biological; D020411:Oligonucleotide Array Sequence Analysis; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism*; D015854:Up-Regulation
C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D053645:Interleukin-2 Receptor alpha Subunit; C524942:MIRN155 microRNA, human; D035683:MicroRNAs