PMID- 20488790
OWN - NLM
STAT- MEDLINE
DCOM- 20100618
LR  - 20211203
IS  - 1550-6606 (Electronic)
IS  - 0022-1767 (Linking)
VI  - 184
IP  - 12
DP  - 2010 Jun 15
TI  - Human CD34-derived myeloid dendritic cell development requires intact 
      phosphatidylinositol 3-kinase-protein kinase B-mammalian target of rapamycin 
      signaling.
PG  - 6600-11
LID - 10.4049/jimmunol.0903089 [doi]
AB  - Dendritic cells (DCs) are composed of different subsets that exhibit distinct 
      functionality in the induction and regulation of immune responses. The myeloid DC 
      subsets, including interstitial DCs and Langerhans cells (LCs), develop from 
      CD34+ hematopoietic progenitors via direct DC precursors or monocytes. The 
      molecular mechanisms regulating DC development are still largely unknown and 
      mostly studied in mice. Phosphatidylinositol 3-kinase (PI3K) regulates multiple 
      processes in myeloid cells. This study investigated the role of PI3K signaling in 
      the development of human CD34-derived myeloid DCs. Pharmacologic inhibition of 
      PI3K or one of its downstream targets mTOR reduced interstitial DC and LC numbers 
      in vitro. Increased activity of this signaling module by introduction of 
      constitutively active protein kinase B (PKB/c-Akt) increased the yields of human 
      DC precursors in vitro as well as in transplanted beta2-microglobulin-/- NOD/SCID 
      mice in vivo. Signaling inhibition during differentiation did not affect the 
      acquisition of a DC phenotype, whereas proliferation and survival strongly 
      depended on intact PI3K-PKB-mTOR signaling. Interestingly, however, this pathway 
      became redundant for survival regulation upon terminal differentiation, which was 
      associated with an altered expression of apoptosis regulating genes. Although 
      dispensable for costimulatory molecule expression, the PI3K-PKB-mTOR signaling 
      module was required for other important processes associated with DC function, 
      including Ag uptake, LPS-induced cytokine secretion, CCR7 expression, and T cell 
      stimulation. Thus, PI3K-PKB-mTOR signaling plays a crucial role in the 
      development of functional CD34-derived myeloid DCs. These findings could be used 
      as a strategy to manipulate DC subset distribution and function to regulate 
      immunity.
FAU - van de Laar, Lianne
AU  - van de Laar L
AD  - Department of Gastroenterology and Hepatology, Erasmus MC-University Medical 
      Center, Rotterdam, The Netherlands.
FAU - Buitenhuis, Miranda
AU  - Buitenhuis M
FAU - Wensveen, Felix M
AU  - Wensveen FM
FAU - Janssen, Harry L A
AU  - Janssen HL
FAU - Coffer, Paul J
AU  - Coffer PJ
FAU - Woltman, Andrea M
AU  - Woltman AM
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20100519
PL  - United States
TA  - J Immunol
JT  - Journal of immunology (Baltimore, Md. : 1950)
JID - 2985117R
RN  - 0 (Antigens, CD34)
RN  - 0 (Intracellular Signaling Peptides and Proteins)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Animals
MH  - Antigens, CD34/immunology/metabolism
MH  - Apoptosis/immunology
MH  - Blotting, Western
MH  - Cell Differentiation/immunology
MH  - Cell Separation
MH  - Dendritic Cells/*cytology/immunology/metabolism
MH  - Flow Cytometry
MH  - Humans
MH  - Intracellular Signaling Peptides and Proteins/immunology/*metabolism
MH  - Mice
MH  - Mice, Inbred NOD
MH  - Mice, SCID
MH  - Myeloid Cells/*cytology/immunology/metabolism
MH  - Phenotype
MH  - Phosphatidylinositol 3-Kinases/immunology/*metabolism
MH  - Protein Serine-Threonine Kinases/immunology/*metabolism
MH  - Proto-Oncogene Proteins c-akt/immunology/*metabolism
MH  - Signal Transduction/*immunology
MH  - TOR Serine-Threonine Kinases
EDAT- 2010/05/22 06:00
MHDA- 2010/06/19 06:00
CRDT- 2010/05/22 06:00
PHST- 2010/05/22 06:00 [entrez]
PHST- 2010/05/22 06:00 [pubmed]
PHST- 2010/06/19 06:00 [medline]
AID - jimmunol.0903089 [pii]
AID - 10.4049/jimmunol.0903089 [doi]
PST - ppublish
SO  - J Immunol. 2010 Jun 15;184(12):6600-11. doi: 10.4049/jimmunol.0903089. Epub 2010 
      May 19.