PMID- 26538392
OWN - NLM
STAT- MEDLINE
DCOM- 20160627
LR  - 20220129
IS  - 1550-6606 (Electronic)
IS  - 0022-1767 (Print)
IS  - 0022-1767 (Linking)
VI  - 195
IP  - 12
DP  - 2015 Dec 15
TI  - MicroRNA-15b/16 Enhances the Induction of Regulatory T Cells by Regulating the 
      Expression of Rictor and mTOR.
PG  - 5667-77
LID - 10.4049/jimmunol.1401875 [doi]
AB  - CD4(+) regulatory T cells (Tregs) are essential for controlling immune responses 
      and preventing autoimmunity. Their development requires regulation of gene 
      expression by microRNAs (miRNAs). To understand miRNA function in Treg 
      development, we searched for important miRNAs and their relevant target genes. Of 
      the more abundantly expressed miRNAs in Tregs, only miR-15b/16, miR-24, and 
      miR-29a impacted the production of in vitro-induced Tregs (iTregs) in 
      overexpression and blocking experiments. miRNA mimics for these significantly 
      enhanced the induction of iTregs in Dicer(-/-) CD4(+) T cells. Furthermore, the 
      overexpression of miR-15b/16 in conventional CD4(+) T cells adoptively 
      transferred into Rag2(-/-) mice increased the in vivo development of peripheral 
      Tregs and diminished the severity of autoimmune colitis. In searching for targets 
      of miR-15b/16, we observed that the mammalian target of rapamycin (mTOR) 
      signaling pathway was enhanced in Dicer(-/-) CD4(+) T cells, and its 
      pharmacological inhibition restored induction of iTregs. Suppression of mTOR 
      signaling is essential for induction of iTregs from naive CD4(+) T cells, and the 
      mTORC2 component, Rictor, contained a functional target site for miR-15b/16. 
      Rictor was more abundantly expressed in Dicer(-/-) T cells as was mTOR, and their 
      expression was downregulated by the overexpression of miR-15b/16. This led to a 
      reduction in mTOR signaling, as measured by phosphorylation of the downstream 
      target, ribosomal protein S6. Finally, knockdown of Rictor by small interfering 
      RNAs enhanced Treg induction in Dicer(-/-) CD4(+) T cells. Therefore, an 
      important mechanism of miRNA regulation of Treg development is through regulation 
      of the mTOR signaling pathway.
CI  - Copyright (c) 2015 by The American Association of Immunologists, Inc.
FAU - Singh, Yogesh
AU  - Singh Y
AUID- ORCID: 0000-0001-6919-6273
AD  - Department of Comparative Biomedical Sciences, The Royal Veterinary College, 
      London NW1 0TU, United Kingdom; Institute of Physiology I, Eberhard Karls 
      University of Tubingen, D-72076 Tubingen, Germany; and.
FAU - Garden, Oliver A
AU  - Garden OA
AD  - Department of Clinical Sciences and Services, The Royal Veterinary College, 
      London NW1 0TU, United Kingdom.
FAU - Lang, Florian
AU  - Lang F
AD  - Institute of Physiology I, Eberhard Karls University of Tubingen, D-72076 
      Tubingen, Germany; and.
FAU - Cobb, Bradley S
AU  - Cobb BS
AUID- ORCID: 0000-0001-6783-0509
AD  - Department of Comparative Biomedical Sciences, The Royal Veterinary College, 
      London NW1 0TU, United Kingdom; bcobb@rvc.ac.uk.
LA  - eng
GR  - BB/F011180/1/BB_/Biotechnology and Biological Sciences Research Council/United 
      Kingdom
GR  - BB/H018573/1/Biotechnology and Biological Sciences Research Council/United 
      Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20151104
PL  - United States
TA  - J Immunol
JT  - Journal of immunology (Baltimore, Md. : 1950)
JID - 2985117R
RN  - 0 (Carrier Proteins)
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (MIRN29 microRNA, mouse)
RN  - 0 (MicroRNAs)
RN  - 0 (Mirn15 microRNA, mouse)
RN  - 0 (Mirn16 microRNA, mouse)
RN  - 0 (Mirn24 microRNA, mouse)
RN  - 0 (RNA, Small Interfering)
RN  - 0 (Rag2 protein, mouse)
RN  - 0 (Rapamycin-Insensitive Companion of mTOR Protein)
RN  - 0 (rictor protein, mouse)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 3.1.26.3 (Ribonuclease III)
SB  - IM
MH  - Adoptive Transfer
MH  - Animals
MH  - Autoimmune Diseases/*immunology
MH  - Carrier Proteins/genetics/*metabolism
MH  - Cell Proliferation
MH  - Cells, Cultured
MH  - Colitis/*immunology
MH  - DNA-Binding Proteins/genetics
MH  - Gene Expression Regulation
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - MicroRNAs/genetics/*metabolism
MH  - RNA, Small Interfering/genetics
MH  - Rapamycin-Insensitive Companion of mTOR Protein
MH  - Ribonuclease III/genetics/*metabolism
MH  - Signal Transduction
MH  - T-Lymphocyte Subsets/*immunology
MH  - T-Lymphocytes, Regulatory/*immunology
MH  - TOR Serine-Threonine Kinases/*metabolism
PMC - PMC4671309
MID - EMS65588
OID - NLM: EMS65588
EDAT- 2015/11/06 06:00
MHDA- 2016/06/28 06:00
PMCR- 2016/06/15
CRDT- 2015/11/06 06:00
PHST- 2014/07/25 00:00 [received]
PHST- 2015/10/09 00:00 [accepted]
PHST- 2015/11/06 06:00 [entrez]
PHST- 2015/11/06 06:00 [pubmed]
PHST- 2016/06/28 06:00 [medline]
PHST- 2016/06/15 00:00 [pmc-release]
AID - jimmunol.1401875 [pii]
AID - 10.4049/jimmunol.1401875 [doi]
PST - ppublish
SO  - J Immunol. 2015 Dec 15;195(12):5667-77. doi: 10.4049/jimmunol.1401875. Epub 2015 
      Nov 4.