PMID- 21480212
OWN - NLM
STAT- MEDLINE
DCOM- 20110909
LR  - 20211203
IS  - 1521-4141 (Electronic)
IS  - 0014-2980 (Linking)
VI  - 41
IP  - 7
DP  - 2011 Jul
TI  - Rapamycin-sensitive signals control TCR/CD28-driven Ifng, Il4 and Foxp3 
      transcription and promoter region methylation.
PG  - 2086-96
LID - 10.1002/eji.201041130 [doi]
AB  - The mammalian target of rapamycin (mTOR) controls T-cell differentiation in 
      response to polarizing cytokines. We previously found that mTOR blockade by 
      rapamycin (RAPA) delays the G1-S cell cycle transition and lymphocyte 
      proliferation. Here, we report that both mTOR complex 1 and mTOR complex 2 are 
      readily activated following TCR/CD28 engagement and are critical for early 
      expression of Ifng, Il4 and Foxp3, and for effector T cell differentiation in the 
      absence of polarizing cytokines. While inhibition of mTOR complex 1 and cell 
      division were evident at low doses of RAPA, inhibition of mTOR complex 2, Ifng, 
      Il4 and Foxp3 expression, and T-cell polarization required higher doses and more 
      prolonged treatments. We found that while T-bet and GATA3 were readily induced 
      following TCR/CD28 engagement, administration of RAPA delayed their expression, 
      and interfered with the loss of DNA methylation within Ifng and Il4 promoter 
      regions. In contrast, RAPA prevented activation-dependent DNA methylation of the 
      Foxp3 promoter favoring Foxp3 expression. As a result, RAPA-cultured cells lacked 
      immediate effector functions and instead were enriched for IL-2+ cells. We 
      propose that mTOR-signaling, by timing the expression of critical transcription 
      factors and DNA methylation of proximal promoter regions, regulates 
      transcriptional competence at immunologically relevant sites and hence lymphocyte 
      differentiation.
CI  - Copyright (c) 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
FAU - Tomasoni, Romana
AU  - Tomasoni R
AD  - Division of Immunology, Transplantation and Infectious Diseases, San Raffaele 
      Scientific Institute, Milan, Italy.
FAU - Basso, Veronica
AU  - Basso V
FAU - Pilipow, Karolina
AU  - Pilipow K
FAU - Sitia, Giovanni
AU  - Sitia G
FAU - Saccani, Simona
AU  - Saccani S
FAU - Agresti, Alessandra
AU  - Agresti A
FAU - Mietton, Flore
AU  - Mietton F
FAU - Natoli, Gioacchino
AU  - Natoli G
FAU - Colombetti, Sara
AU  - Colombetti S
FAU - Mondino, Anna
AU  - Mondino A
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - Germany
TA  - Eur J Immunol
JT  - European journal of immunology
JID - 1273201
RN  - 0 (CD28 Antigens)
RN  - 0 (Cytokines)
RN  - 0 (Forkhead Transcription Factors)
RN  - 0 (Foxp3 protein, mouse)
RN  - 0 (GATA3 Transcription Factor)
RN  - 0 (Gata3 protein, mouse)
RN  - 0 (Interleukin-2)
RN  - 0 (Multiprotein Complexes)
RN  - 0 (Proteins)
RN  - 0 (T-Box Domain Proteins)
RN  - 0 (T-box transcription factor TBX21)
RN  - 207137-56-2 (Interleukin-4)
RN  - 82115-62-6 (Interferon-gamma)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Animals
MH  - CD28 Antigens/*metabolism
MH  - CD4-Positive T-Lymphocytes/*immunology/metabolism
MH  - Cell Differentiation
MH  - Cells, Cultured
MH  - Cytokines/metabolism
MH  - DNA Methylation
MH  - Forkhead Transcription Factors/*genetics/metabolism
MH  - GATA3 Transcription Factor/biosynthesis
MH  - Interferon-gamma/*genetics/metabolism
MH  - Interleukin-2/biosynthesis
MH  - Interleukin-4/*genetics/metabolism
MH  - Lymphocyte Activation
MH  - Mechanistic Target of Rapamycin Complex 1
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Multiprotein Complexes
MH  - Polymerase Chain Reaction
MH  - Promoter Regions, Genetic
MH  - Proteins/metabolism
MH  - Signal Transduction
MH  - Sirolimus/*pharmacology
MH  - T-Box Domain Proteins/biosynthesis
MH  - TOR Serine-Threonine Kinases/metabolism
MH  - *Transcription, Genetic
EDAT- 2011/04/12 06:00
MHDA- 2011/09/10 06:00
CRDT- 2011/04/12 06:00
PHST- 2011/04/12 06:00 [entrez]
PHST- 2011/04/12 06:00 [pubmed]
PHST- 2011/09/10 06:00 [medline]
AID - 10.1002/eji.201041130 [doi]
PST - ppublish
SO  - Eur J Immunol. 2011 Jul;41(7):2086-96. doi: 10.1002/eji.201041130.