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J Immunol. 2014 Jun 15;192(12):5963-73. doi: 10.4049/jimmunol.1303058. Epub 2014 May 9.

RNA and imidazoquinolines are sensed by distinct TLR7/8 ectodomain sites resulting in functionally disparate signaling events.

Author information

1
Junior Research Group Toll-Like Receptors and Cancer, German Cancer Research Center, 69120 Heidelberg, Germany;
2
Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, United Kingdom; alexander.weber@uni-tuebingen.de alison.simmons@ndm.ox.ac.uk al.leslie@k-rith.org.
3
Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, United Kingdom;
4
Department of Immunology, Interfaculty Institute for Cell Biology, University of Tübingen, 72076 Tübingen, Germany;
5
Department of Genetics, The Scripps Research Institute, La Jolla, CA 92037;
6
Department of Pediatrics I, University of Tübingen, 72076 Tübingen, Germany;
7
Wellcome Trust Centre for Human Genetics, University of Oxford, Headington, Oxford OX3 7BN, United Kingdom;
8
Core Facility Molecular Structure Analysis, German Cancer Research Center, 69120 Heidelberg, Germany;
9
Institut National de la Santé et de la Recherché Médicale, Unité 1151, 75015 Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine Paris Descartes, 75015 Paris, France; and.
10
Center for Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390.
11
Junior Research Group Toll-Like Receptors and Cancer, German Cancer Research Center, 69120 Heidelberg, Germany; Department of Immunology, Interfaculty Institute for Cell Biology, University of Tübingen, 72076 Tübingen, Germany;

Abstract

TLRs 7 and 8 are pattern recognition receptors controlling antiviral host defense or autoimmune diseases. Apart from foreign and host RNA, synthetic RNA oligoribonucleotides (ORN) or small molecules of the imidazoquinoline family activate TLR7 and 8 and are being developed as therapeutic agonists. The structure-function relationships for RNA ORN and imidazoquinoline sensing and consequent downstream signaling by human TLR7 and TLR8 are unknown. Proteome- and genome-wide analyses in primary human monocyte-derived dendritic cells here showed that TLR8 sensing of RNA ORN versus imidazoquinoline translates to ligand-specific differential phosphorylation and transcriptional events. In addition, TLR7 and 8 ectodomains were found to discriminate between RNA ORN and imidazoquinolines by overlapping and nonoverlapping recognition sites to which murine loss-of-function mutations and human naturally occurring hyporesponsive polymorphisms map. Our data suggest TLR7 and TLR8 can signal in two different "modes" depending on the class of ligand. Considering RNA ORN and imidazoquinolines have been regarded as functionally interchangeable, our study highlights important functional incongruities whose understanding will be important for developing TLR7 or 8 therapeutics with desirable effector and safety profiles for in vivo application.

PMID:
24813206
PMCID:
PMC4066583
DOI:
10.4049/jimmunol.1303058
[Indexed for MEDLINE]
Free PMC Article

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