PMID- 18253710
OWN - NLM
STAT- MEDLINE
DCOM- 20080825
LR  - 20211020
IS  - 0946-2716 (Print)
IS  - 1432-1440 (Electronic)
IS  - 0946-2716 (Linking)
VI  - 86
IP  - 4
DP  - 2008 Apr
TI  - TLR-mediated induction of negative regulatory ligands on dendritic cells.
PG  - 443-55
LID - 10.1007/s00109-008-0310-x [doi]
AB  - Dendritic cells (DCs) shape T-cell response patterns and determine early, 
      intermediate, and late outcomes of immune recognition events. They either 
      facilitate immunostimulation or induce tolerance, possibly determined by initial 
      DC activation signals, such as binding Toll-like receptor (TLR) ligands. Here, we 
      report that DC stimulation through the TLR3 ligand dsRNA [poly(I:C)] limits CD4 
      T-cell proliferation, curtailing adaptive immune responses. CD4+ T cells 
      instructed by either lipopolysaccharide (LPS) or poly(I:C)-conditioned DCs 
      promptly upregulated the activation marker CD69. Whereas LPS-pretreated DCs 
      subsequently sustained T-cell clonal expansion, proliferation of CD4+ T cells 
      exposed to poly(I:C)-pretreated DCs was markedly suppressed. This proliferative 
      defect required DC-T cell contact, was independent of IFN-alpha, and was overcome 
      by exogenous IL-2, indicating T-cell anergy. Coinciding with the downregulation, 
      CD4+ T cells expressed the inhibitory receptor PD-1. Antibodies blocking the PD-1 
      ligand PD-L1 restored proliferation. dsRNA-stimulated DCs preferentially induced 
      PD-L1, whereas poly(I:C) and LPS both upregulated the costimulatory molecule CD86 
      to a comparable extent. Poly(dA-dT), a ligand targeting the cytoplasmic RNA 
      helicase pattern-recognition pathway, failed to selectively induce PD-L1 
      upregulation, assigning this effect to the TLR3 pathway. Poly(I:C)-conditioned 
      DCs promoted accumulation of phosphorylated SHP-2, the intracellular phosphatase 
      mediating PD-1 inhibitory effects. The ability of dsRNA to bias DC 
      differentiation toward providing inhibitory signals to interacting CD4+ T cells 
      may be instrumental in viral immune evasion. Conversely, TLR3 ligands may have 
      therapeutic value in silencing pathogenic immune responses.
FAU - Groschel, Stefan
AU  - Groschel S
AD  - Kathleen B. and Mason I. Lowance Center for Human Immunology, Department of 
      Medicine, Emory University School of Medicine, Room 1003 Woodruff Memorial 
      Research Building, 101 Woodruff Circle, Atlanta, GA 30322, USA.
FAU - Piggott, Kisha D
AU  - Piggott KD
FAU - Vaglio, Augusto
AU  - Vaglio A
FAU - Ma-Krupa, Wei
AU  - Ma-Krupa W
FAU - Singh, Karnail
AU  - Singh K
FAU - Goronzy, Jorg J
AU  - Goronzy JJ
FAU - Weyand, Cornelia M
AU  - Weyand CM
LA  - eng
GR  - R01 AG 15043/AG/NIA NIH HHS/United States
GR  - M01 RR00039/RR/NCRR NIH HHS/United States
GR  - R01 AR 41974/AR/NIAMS NIH HHS/United States
GR  - R01 AI044142/AI/NIAID NIH HHS/United States
GR  - R01 AR 42527/AR/NIAMS NIH HHS/United States
GR  - R01 AR041974-14/AR/NIAMS NIH HHS/United States
GR  - R01 AR042527-13/AR/NIAMS NIH HHS/United States
GR  - UL1 TR000454/TR/NCATS NIH HHS/United States
GR  - U19 AI057266-03/AI/NIAID NIH HHS/United States
GR  - R01 EY011916/EY/NEI NIH HHS/United States
GR  - R01 AG015043-10/AG/NIA NIH HHS/United States
GR  - U19 AI057266-05S10003/AI/NIAID NIH HHS/United States
GR  - U19 AI057266/AI/NIAID NIH HHS/United States
GR  - R01 AR042527/AR/NIAMS NIH HHS/United States
GR  - R01 AI044142-09/AI/NIAID NIH HHS/United States
GR  - R01 EY 11916/EY/NEI NIH HHS/United States
GR  - M01 RR000039/RR/NCRR NIH HHS/United States
GR  - R01 AR041974/AR/NIAMS NIH HHS/United States
GR  - R56 AI044142/AI/NIAID NIH HHS/United States
GR  - M01 RR000039-47/RR/NCRR NIH HHS/United States
GR  - R01 AI 57266/AI/NIAID NIH HHS/United States
GR  - U19 AI 44142/AI/NIAID NIH HHS/United States
GR  - R01 EY011916-11A1/EY/NEI NIH HHS/United States
GR  - R01 AG015043/AG/NIA NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20080206
PL  - Germany
TA  - J Mol Med (Berl)
JT  - Journal of molecular medicine (Berlin, Germany)
JID - 9504370
RN  - 0 (Interferon-alpha)
RN  - 0 (Ligands)
RN  - 0 (Lipopolysaccharides)
RN  - 0 (RNA, Double-Stranded)
RN  - 0 (Toll-Like Receptor 3)
SB  - IM
MH  - CD4-Positive T-Lymphocytes/immunology
MH  - Dendritic Cells/*immunology
MH  - Humans
MH  - Interferon-alpha/immunology
MH  - *Ligands
MH  - Lipopolysaccharides/immunology
MH  - RNA, Double-Stranded/genetics/metabolism
MH  - Toll-Like Receptor 3/*immunology
PMC - PMC2556182
MID - NIHMS65856
EDAT- 2008/02/07 09:00
MHDA- 2008/08/30 09:00
PMCR- 2009/04/01
CRDT- 2008/02/07 09:00
PHST- 2007/10/09 00:00 [received]
PHST- 2008/01/07 00:00 [accepted]
PHST- 2007/12/21 00:00 [revised]
PHST- 2008/02/07 09:00 [pubmed]
PHST- 2008/08/30 09:00 [medline]
PHST- 2008/02/07 09:00 [entrez]
PHST- 2009/04/01 00:00 [pmc-release]
AID - 10.1007/s00109-008-0310-x [doi]
PST - ppublish
SO  - J Mol Med (Berl). 2008 Apr;86(4):443-55. doi: 10.1007/s00109-008-0310-x. Epub 
      2008 Feb 6.