PMID- 20805416
OWN - NLM
STAT- MEDLINE
DCOM- 20101019
LR  - 20211203
IS  - 1550-6606 (Electronic)
IS  - 0022-1767 (Linking)
VI  - 185
IP  - 7
DP  - 2010 Oct 1
TI  - A versatile role of mammalian target of rapamycin in human dendritic cell 
      function and differentiation.
PG  - 3919-31
LID - 10.4049/jimmunol.1000296 [doi]
AB  - The mammalian target of rapamycin (mTOR) regulates cell growth and survival and 
      exists as rapamycin-sensitive mTOR complex (mTORC) 1 and as rapamycin-insensitive 
      mTORC2. Although mTOR is a well-known regulator of diverse immune cells, its 
      detailed role in human dendritic cell (DC) function and differentiation is only 
      incompletely understood. In this study, we demonstrate divergent roles of mTOR 
      during activation and differentiation of myeloid DCs (mDCs) and monocyte-derived 
      DCs (moDCs). Inhibition of mTORC1 in mDCs activated with TLR-dependent or 
      -independent stimuli increased proinflammatory cytokines and NF-kappaB, whereas IL-10 
      and STAT3 were blocked. Rapamycin regulated the costimulatory/surface molecules 
      CD86, programmed death ligand-1, and CD25 on mDCs and significantly increased the 
      T cell allostimulatory potential of mDCs. In contrast, rapamycin suppressed 
      immunostimulatory molecules and the allostimulatory potential of LPS-stimulated 
      moDCs by an inability to augment NF-kappaB signaling. In differentiating moDCs, the 
      PI3K/Akt-dependent mTOR pathway was constitutively activated by GM-CSF to induce 
      DC differentiation in an mTORC1-dependent manner. Inhibition of mTORC1 or 
      mTORC1/2 during moDC differentiation decreased moDC survival and markedly 
      hampered its immunostimulatory phenotype. Analyzing the fate of DCs in vivo, we 
      found that kidney transplant patients treated with rapamycin displayed an 
      increased immunostimulatory potential of mDCs compared with patients treated with 
      calcineurin inhibitors. Furthermore, rapamycin did not interfere with mDC 
      differentiation in these patients. Collectively, mTOR exerts divergent 
      immunoregulatory functions during DC activation and differentiation depending on 
      the DC type that lead to opposing T cell responses, which might be of clinical 
      importance in transplantation, cancer, and also for novel vaccination strategies.
FAU - Haidinger, Michael
AU  - Haidinger M
AD  - Clinical Division of Nephrology and Dialysis, Department of Internal Medicine 
      III, Medical University of Vienna, Vienna, Austria.
FAU - Poglitsch, Marko
AU  - Poglitsch M
FAU - Geyeregger, Rene
AU  - Geyeregger R
FAU - Kasturi, Sudhir
AU  - Kasturi S
FAU - Zeyda, Maximilian
AU  - Zeyda M
FAU - Zlabinger, Gerhard J
AU  - Zlabinger GJ
FAU - Pulendran, Bali
AU  - Pulendran B
FAU - Horl, Walter H
AU  - Horl WH
FAU - Saemann, Marcus D
AU  - Saemann MD
FAU - Weichhart, Thomas
AU  - Weichhart T
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20100830
PL  - United States
TA  - J Immunol
JT  - Journal of immunology (Baltimore, Md. : 1950)
JID - 2985117R
RN  - 0 (Cytokines)
RN  - 0 (Intracellular Signaling Peptides and Proteins)
RN  - 0 (NF-kappa B)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Cell Differentiation/*immunology
MH  - Cell Separation
MH  - Cytokines/biosynthesis/immunology
MH  - Dendritic Cells/cytology/*immunology/metabolism
MH  - Enzyme-Linked Immunosorbent Assay
MH  - Female
MH  - Flow Cytometry
MH  - Humans
MH  - Intracellular Signaling Peptides and Proteins/*immunology/metabolism
MH  - Kidney Transplantation/immunology
MH  - Male
MH  - Microscopy, Fluorescence
MH  - Middle Aged
MH  - NF-kappa B/immunology/metabolism
MH  - Protein Serine-Threonine Kinases/*immunology/metabolism
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - Signal Transduction/*immunology
MH  - TOR Serine-Threonine Kinases
EDAT- 2010/09/02 06:00
MHDA- 2010/10/20 06:00
CRDT- 2010/09/01 06:00
PHST- 2010/09/01 06:00 [entrez]
PHST- 2010/09/02 06:00 [pubmed]
PHST- 2010/10/20 06:00 [medline]
AID - jimmunol.1000296 [pii]
AID - 10.4049/jimmunol.1000296 [doi]
PST - ppublish
SO  - J Immunol. 2010 Oct 1;185(7):3919-31. doi: 10.4049/jimmunol.1000296. Epub 2010 
      Aug 30.