Format

Send to

Choose Destination
Nat Microbiol. 2019 Nov 4. doi: 10.1038/s41564-019-0594-3. [Epub ahead of print]

Asymmetric distribution of TLR3 leads to a polarized immune response in human intestinal epithelial cells.

Author information

1
Schaller Research Group at CellNetworks, Department of Infectious Diseases, Virology, Heidelberg University Hospital, Heidelberg, Germany. m.stanifer@dkfz.de.
2
Schaller Research Group at CellNetworks, Department of Infectious Diseases, Virology, Heidelberg University Hospital, Heidelberg, Germany.
3
Laboratory for Intestinal Ecosystem, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
4
Department of Infectious Diseases, King's College London, London, UK.
5
Division of Biostatistics, DKFZ, Heidelberg, Germany.
6
Department of Molecular Pharmacology and Cell Biology, Leibniz-Forschungsinstitut für Molekulare Pharmakologie and Faculty of Biology, Chemistry and Pharmacy, Freie Universität Berlin, Berlin, Germany.
7
Harvard Medical School and Division of Gastroenterology, Boston Children's Hospital, Boston, MA, USA.
8
Research Centre for Infectious Diseases, Institute for Molecular Infection Biology, Julius-Maximilians-University of Wuerzburg, Wuerzburg, Germany.
9
Schaller Research Group at CellNetworks, Department of Infectious Diseases, Virology, Heidelberg University Hospital, Heidelberg, Germany. s.boulant@dkfz.de.
10
Research Group "Cellular polarity and viral infection", DKFZ, Heidelberg, Germany. s.boulant@dkfz.de.

Abstract

Intestinal epithelial cells (IECs) act as a physical barrier separating the commensal-containing intestinal tract from the sterile interior. These cells have found a complex balance allowing them to be prepared for pathogen attacks while still tolerating the presence of bacterial or viral stimuli present in the lumen of the gut. Using primary human IECs, we probed the mechanisms that allow for such a tolerance. We discovered that viral infections emanating from the basolateral side of IECs elicit a stronger intrinsic immune response in comparison to lumenal apical infections. We determined that this asymmetric immune response is driven by the clathrin-sorting adaptor AP-1B, which mediates the polarized sorting of Toll-like receptor 3 (TLR3) towards the basolateral side of IECs. Mice and human IECs lacking AP-1B showed an exacerbated immune response following apical stimulation. Together, these results suggest a model where the cellular polarity program plays an integral role in the ability of IECs to partially tolerate apical commensals while remaining fully responsive to invasive basolateral pathogens.

PMID:
31686029
DOI:
10.1038/s41564-019-0594-3

Supplemental Content

Full text links

Icon for Nature Publishing Group
Loading ...
Support Center