PMID- 28630093
OWN - NLM
STAT- MEDLINE
DCOM- 20170928
LR  - 20180127
IS  - 1550-6606 (Electronic)
IS  - 0022-1767 (Linking)
VI  - 199
IP  - 2
DP  - 2017 Jul 15
TI  - Dendritic Cell Sensing of Hydrophobic Di- and Triacylated Lipopeptides 
      Self-Assembled within Synthetic Virus-like Particles.
PG  - 734-749
LID - 10.4049/jimmunol.1600521 [doi]
AB  - Dendritic cells (DCs) play critical roles in developing immune defenses. One 
      important aspect is interaction with pathogen-associated molecular patterns 
      (PAMPs)/danger-associated molecular patterns, including di- and triacylated 
      lipopeptides. Isolated or synthetic lipopeptides are potent vaccine adjuvants, 
      interacting with cell surface TLR2 heterodimers. In contrast, deep embedment 
      within bacteria cell walls would impair lipopeptide interaction with cell surface 
      TLR2, requiring degradation for PAMP recognition. Accordingly, DC processing in 
      the absence of surface TLR2 ligation was defined using synthetic virus-like 
      particles (SVLPs) carrying hydrophobic TLR2 PAMPs within di- and triacylated 
      lipopeptide cores (P2Cys-SVLPs and P3Cys-SVLPs) compared with SVLPs lacking 
      immunomodulatory lipopeptides. DCs rapidly and efficiently internalized SVLPs, 
      which was dominated by slow endocytic processing via macropinocytosis, although 
      some caveolar endocytosis was implicated. This delivered SVLPs primarily into 
      macropinosomes often interacting with EEA-1(+) early endosomes. Although 
      endoplasmic reticulum association was occasionally noted, association with 
      recycling/sorting structures was not observed. Involvement of LysoTracker(+) 
      structures slowly increased with time, with SVLPs present in such structures 
      ultimately dominating. Only SVLPs carrying di- and triacylated lipopeptide cores 
      induced DC activation and maturation independently of surface TLR2 ligation. 
      Intracellular recognition of SVLP TLR2 ligands was confirmed by observing SVLPs' 
      association with internal TLR2, which had similar kinetics to SVLP association 
      with LysoTracker. This related to inflammatory cytokine induction by SVLP(+) DCs, 
      with adaptive immune response activation ex vivo/in vivo. Importantly, particular 
      DCs, not monocytes, recognized intracellular exposure of the TLR2 PAMPs carried 
      by di- and triacylated SVLP cores, which indicates subset-distinct recognition of 
      functional internal TLR2 ligands. Thus, vaccines carrying hydrophobic TLR2 
      ligands would interact with particular DCs for efficient induction of specific 
      immunity in the absence of additional adjuvant.
CI  - Copyright (c) 2017 by The American Association of Immunologists, Inc.
FAU - Sharma, Rajni
AU  - Sharma R
AUID- ORCID: 0000-0003-0051-2308
AD  - Institute of Virology and Immunology, 3147 Mittelhausern, Switzerland.
FAU - Ghasparian, Arin
AU  - Ghasparian A
AUID- ORCID: 0000-0002-0100-7461
AD  - Department of Chemistry, University of Zurich, 8057 Zurich, Switzerland; and.
AD  - Virometix AG, 8952 Zurich, Switzerland.
FAU - Robinson, John A
AU  - Robinson JA
AD  - Department of Chemistry, University of Zurich, 8057 Zurich, Switzerland; and.
FAU - McCullough, Kenneth C
AU  - McCullough KC
AUID- ORCID: 0000-0001-5325-6761
AD  - Institute of Virology and Immunology, 3147 Mittelhausern, Switzerland; 
      kmc.projects1@gmail.com.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20170619
PL  - United States
TA  - J Immunol
JT  - Journal of immunology (Baltimore, Md. : 1950)
JID - 2985117R
RN  - 0 (Adjuvants, Immunologic)
RN  - 0 (Cytokines)
RN  - 0 (Lipopeptides)
RN  - 0 (Pathogen-Associated Molecular Pattern Molecules)
RN  - 0 (Toll-Like Receptor 2)
RN  - 0 (Vaccines, Virus-Like Particle)
SB  - IM
MH  - Adaptive Immunity
MH  - Adjuvants, Immunologic
MH  - Animals
MH  - Cell Differentiation
MH  - Cytokines/immunology
MH  - Dendritic Cells/*immunology/metabolism
MH  - Endocytosis
MH  - Endoplasmic Reticulum/immunology/physiology
MH  - Endosomes/immunology/metabolism
MH  - Lipopeptides/*chemistry/immunology
MH  - Mice
MH  - Monocytes/immunology/metabolism
MH  - Pathogen-Associated Molecular Pattern Molecules/chemistry/*immunology/metabolism
MH  - Sus scrofa
MH  - Toll-Like Receptor 2/immunology/metabolism
MH  - Vaccines, Virus-Like Particle/administration & dosage/chemistry/*immunology
EDAT- 2017/06/21 06:00
MHDA- 2017/09/29 06:00
CRDT- 2017/06/21 06:00
PHST- 2016/04/14 00:00 [received]
PHST- 2017/05/18 00:00 [accepted]
PHST- 2017/06/21 06:00 [pubmed]
PHST- 2017/09/29 06:00 [medline]
PHST- 2017/06/21 06:00 [entrez]
AID - jimmunol.1600521 [pii]
AID - 10.4049/jimmunol.1600521 [doi]
PST - ppublish
SO  - J Immunol. 2017 Jul 15;199(2):734-749. doi: 10.4049/jimmunol.1600521. Epub 2017 
      Jun 19.