Abstract
Gram+ infections are worldwide life-threatening diseases in which the pathological role of type I interferon (IFN) has been highlighted. Plasmacytoid predendritic cells (pDCs) produce high amounts of type I IFN following viral sensing. Despite studies suggesting that pDCs respond to bacteria, the mechanisms underlying bacterial sensing in pDCs are unknown. We show here that human primary pDCs express toll-like receptor 1 (TLR1) and 2 (TLR2) and respond to bacterial lipoproteins. We demonstrated that pDCs differentially respond to gram+ bacteria through the TLR1/2 pathway. Notably, up-regulation of costimulatory molecules and pro-inflammatory cytokines was TLR1 dependent, whereas type I IFN secretion was TLR2 dependent. Mechanistically, we demonstrated that these differences relied on diverse signaling pathways activated by TLR1/2. MAPK and NF-κB pathways were engaged by TLR1, whereas the Phosphoinositide 3-kinase (PI3K) pathway was activated by TLR2. This dichotomy was reflected in a different role of TLR2 and TLR1 in pDC priming of naïve cluster of differentiation 4+ (CD4+) T cells, and T helper (Th) cell differentiation. This work provides the rationale to explore and target pDCs in bacterial infection.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Cell Differentiation / physiology
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Cytokines / metabolism
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Dendritic Cells / metabolism*
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Dendritic Cells / microbiology
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Dendritic Cells / pathology
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Gram-Positive Bacterial Infections / metabolism*
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Gram-Positive Bacterial Infections / pathology
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Healthy Volunteers
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Humans
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Interferon-alpha / metabolism
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Lymphocyte Activation
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Mitogen-Activated Protein Kinase 1 / metabolism
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NF-kappa B / metabolism
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Phosphatidylinositol 3-Kinases / metabolism
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Signal Transduction
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T-Lymphocytes / immunology
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Toll-Like Receptor 1 / metabolism*
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Toll-Like Receptor 2 / metabolism*
Substances
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Cytokines
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Interferon-alpha
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NF-kappa B
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TLR1 protein, human
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TLR2 protein, human
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Toll-Like Receptor 1
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Toll-Like Receptor 2
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Mitogen-Activated Protein Kinase 1
Grants and funding
This work was supported by funding from INSERM (BIO2014-08) (
www.inserm.fr), Agence nationale de la recherche (
http://www.agence-nationale-recherche.fr/) ANR-13-BSV1-0024-02, ANR-10-IDEX-0001-02 PSL* and ANR-11-LABX-0043, ERC (erc.europa.eu) (IT-DC 281987 and HEALTH 2011-261366) and CIC IGR-Curie 1428 (
www.curie.fr). S.R. was supported by MESR - Ministry of Higher Education and Research of France, MESR fellowship (
http://www.enseignementsup-recherche.gouv.fr/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.