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Toll-like receptor 3 promotes cross-priming to virus-infected cells

Nature volume 433, pages 887–892 (2005)Cite this article

Abstract

Cross-presentation of cell-associated antigens plays an important role in regulating CD8+ T cell responses to proteins that are not expressed by antigen-presenting cells (APCs)1. Dendritic cells are the principal cross-presenting APCs in vivo and much progress has been made in elucidating the pathways that allow dendritic cells to capture and process cellular material1. However, little is known about the signals that determine whether such presentation ultimately results in a cytotoxic T cell (CTL) response (cross-priming) or in CD8+ T cell inactivation (cross-tolerance). Here we describe a mechanism that promotes cross-priming during viral infections. We show that murine CD8α+ dendritic cells are activated by double-stranded (ds)RNA present in virally infected cells but absent from uninfected cells. Dendritic cell activation requires phagocytosis of infected material, followed by signalling through the dsRNA receptor, toll-like receptor 3 (TLR3). Immunization with virus-infected cells or cells containing synthetic dsRNA leads to a striking increase in CTL cross-priming against cell-associated antigens, which is largely dependent on TLR3 expression by antigen-presenting cells. Thus, TLR3 may have evolved to permit cross-priming of CTLs against viruses that do not directly infect dendritic cells.

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Figure 1: In vitro activation of CD8α+ DCs by poly I:C-loaded or virally infected cells.
Figure 2: CD8α+ DC activation by poly I:C-loaded or virally infected cells requires endosomal recognition by TLR3.
Figure 3: dsRNA or viral infection promotes in vivo CTL cross-priming to cell-associated antigen.
Figure 4: TLR3 dependence of CTL cross-priming against dsRNA-loaded or virally infected cells.

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Acknowledgements

This work was funded by Cancer Research UK (C.R.S.) and by the Swedish Research Council and the EU program (P.L.). We thank I. Kerr for providing EMCV and anti-EMCV antiserum, L. van Dinten for suggestions on ‘suicide’ virus models and L. Kostic for technical assistance. We are grateful to R. Germain, I. Kerr and members of the Immunobiology Laboratory, Cancer Research UK, for advice and critical review of the manuscript. R.A.F. is an investigator of the Howard Hughes Medical Institute, M.A.N. is supported by an EMBO long-term fellowship and Y.T.A. is supported by the Nakatomi Foundation.

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Author notes

  1. Lena Alexopoulou

    Present address: Centre d'Immunologie de Marseille-Luminy, CNRS-INSERM, Parc Scientifique et Technologique de Luminy – Case 906, 13009, Marseille, France

  2. Oliver Schulz and Sandra S. Diebold: These authors contributed equally to this work

Authors and Affiliations

  1. Immunobiology Laboratory, Cancer Research UK London Research Institute, Lincoln's Inn Fields Laboratories, 44 Lincoln's Inn Fields, WC2A 3PX, London, UK

    Oliver Schulz, Sandra S. Diebold, Martijn A. Nolte & Caetano Reis e Sousa

  2. Microbiology and Tumor Biology Center, Karolinska Institutet, Nobelsväg 16, Solna, SE-171 77, Stockholm, Sweden

    Margaret Chen, Tanja I. Näslund & Peter Liljeström

  3. Department of Vaccine Research at Swedish Institute for Infectious Disease Control, Nobelsväg 18, 171 77, Stockholm, Sweden

    Margaret Chen & Peter Liljeström

  4. Section of Immunobiology, Yale University School of Medicine and Howard Hughes Medical Institute, 330 Cedar Street, PO Box 208011, New Haven, Connecticut, 06520, USA

    Lena Alexopoulou, Yasu-Taka Azuma & Richard A. Flavell

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Correspondence to Caetano Reis e Sousa.

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Supplementary information

Supplementary Figures 1-7

This file contains Supplementary Figures 1 (expression of TLR3 is restricted to CD8α+ DC), 2 (phagocytosis by CD8α+DC is unaffected by poly I:C within target cells), 3 (unirradiated cells loaded with poly I:C promote activation of CD8α+DC), 4 (CD8α+DC are highly resistant to infection by EMCV or SFV), 5 (quantitation of cell-associated OVA), 6 (induction of CTL cross-priming with dsRNA-bearing cells) and 7 (Tlr3-/- chimeric mice do not show a generic defect in CTL cross-priming). (PDF 1639 kb)

Supplementary Figure Legends

This file contains legends for Supplementary Figures 1-7. (DOC 28 kb)

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Schulz, O., Diebold, S., Chen, M. et al. Toll-like receptor 3 promotes cross-priming to virus-infected cells. Nature 433, 887–892 (2005). https://doi.org/10.1038/nature03326

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