BAD-LAMP controls TLR9 trafficking and signalling in human plasmacytoid dendritic cells

Alexis Combes, Voahirana Camosseto, Prudence N’Guessan, Rafael J. Argüello, Julie Mussard, Christophe Caux, Nathalie Bendriss-Vermare, Philippe Pierre and Evelina Gatti ()
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Alexis Combes: Aix Marseille Université, CNRS, INSERM, CIML
Voahirana Camosseto: Aix Marseille Université, CNRS, INSERM, CIML
Prudence N’Guessan: Aix Marseille Université, CNRS, INSERM, CIML
Rafael J. Argüello: Aix Marseille Université, CNRS, INSERM, CIML
Julie Mussard: Centre Léon Berard
Christophe Caux: Centre Léon Berard
Nathalie Bendriss-Vermare: Centre Léon Berard
Philippe Pierre: Aix Marseille Université, CNRS, INSERM, CIML
Evelina Gatti: Aix Marseille Université, CNRS, INSERM, CIML

Nature Communications, 2017, vol. 8, issue 1, 1-18

Abstract: Abstract Toll-like receptors (TLR) are essential components of the innate immune system. Several accessory proteins, such as UNC93B1, are required for transport and activation of nucleic acid sensing Toll-like receptors in endosomes. Here, we show that BAD-LAMP (LAMP5) controls TLR9 trafficking to LAMP1+ late endosomes in human plasmacytoid dendritic cells (pDC), leading to NF-κB activation and TNF production upon DNA detection. An inducible VAMP3+/LAMP2+/LAMP1− endolysosome compartment exists in pDCs from which TLR9 activation triggers type I interferon expression. BAD-LAMP-silencing enhances TLR9 retention in this compartment and consequent downstream signalling events. Conversely, sustained BAD-LAMP expression in pDCs contributes to their lack of type I interferon production after exposure to a TGF-β-positive microenvironment or isolation from human breast tumours. Hence, BAD-LAMP limits interferon expression in pDCs indirectly, by promoting TLR9 sorting to late endosome compartments at steady state and in response to immunomodulatory cues.

Date: 2017
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DOI: 10.1038/s41467-017-00695-1

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