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Intracellular localization of Toll-like receptor 9 prevents recognition of self DNA but facilitates access to viral DNA

Nature Immunology volume 7, pages 49–56 (2006)Cite this article

Abstract

Toll-like receptors (TLRs) sense infection by detecting molecular structures of microbial origin. TLR3, TLR7 and TLR9 recognize nucleic acids and are localized to intracellular compartments where they normally respond to viral nucleic acids. The purpose for this intracellular localization, however, is not clear. Here we describe a chimeric TLR9 receptor that localized to the cell surface and responded normally to synthetic TLR9 ligands but not to viral nucleic acids. However, the 'relocated' chimeric TLR9 receptor was able to recognize self DNA, which does not stimulate wild-type TLR9. These data demonstrated that intracellular localization of TLR9 was not required for ligand recognition. Instead, localization of the nucleic acid-sensing TLRs is critical in discriminating between self and nonself nucleic acid.

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Figure 1: Defining the TLR domains responsible for localization.
Figure 2: The TLR9N4C chimeric receptor is expressed at cell surface.
Figure 3: Relocalized TLR9 responds to CpG DNA independently of endosomal acidification.
Figure 4: The intracellular localization of TLR9 is necessary for recognition of viral DNA.
Figure 5: TLR9N4C recognizes self DNA.

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Acknowledgements

We thank S. Akira for TLR9-deficient mice; A. Iwasaki for HSV-2; A. Unni, C. Pasare and A. Rudensky for discussions and advice; and W. Yuan for technical advice. R.M. is an investigator of the Howard Hughes Medical Institute. Supported by the National Institutes of Health (AI46688 and AI055502 to R.M. and AI07019 to J.K.).

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  1. Gregory M Barton

    Present address: Department of Molecular and Cell Biology, University of California Berkeley, Berkeley, California, 94720, USA

Authors and Affiliations

  1. Section of Immunobiology, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, 06520-8011, Connecticut, USA

    Gregory M Barton, Jonathan C Kagan & Ruslan Medzhitov

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  2. Jonathan C Kagan
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Correspondence to Ruslan Medzhitov.

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Supplementary information

Supplementary Fig. 1

Immunofluorescence images of MEFs expressing CD4-TLR4 (left), ARF1T31N (center), and the merged image (right). (PDF 156 kb)

Supplementary Fig. 2

The TLR4-T4TM chimeric receptor does not signal. (PDF 226 kb)

Supplementary Fig. 3

TLR9N4C does not signal in pDC. (PDF 298 kb)

Supplementary Fig. 4

Equivalent expression of TLR9 and TLR9N4C from bicistronic retroviral vectors. (PDF 228 kb)

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Barton, G., Kagan, J. & Medzhitov, R. Intracellular localization of Toll-like receptor 9 prevents recognition of self DNA but facilitates access to viral DNA. Nat Immunol 7, 49–56 (2006). https://doi.org/10.1038/ni1280

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