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Systemic activation of dendritic cells by Toll-like receptor ligands or malaria infection impairs cross-presentation and antiviral immunity

Nature Immunology volume 7, pages 165–172 (2006)Cite this article

Abstract

The mechanisms responsible for the immunosuppression associated with sepsis or some chronic blood infections remain poorly understood. Here we show that infection with a malaria parasite (Plasmodium berghei) or simple systemic exposure to bacterial or viral Toll-like receptor ligands inhibited cross-priming. Reduced cross-priming was a consequence of downregulation of cross-presentation by activated dendritic cells due to systemic activation that did not otherwise globally inhibit T cell proliferation. Although activated dendritic cells retained their capacity to present viral antigens via the endogenous major histocompatibility complex class I processing pathway, antiviral responses were greatly impaired in mice exposed to Toll-like receptor ligands. This is consistent with a key function for cross-presentation in antiviral immunity and helps explain the immunosuppressive effects of systemic infection. Moreover, inhibition of cross-presentation was overcome by injection of dendritic cells bearing antigen, which provides a new strategy for generating immunity during immunosuppressive blood infections.

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Figure 1: DCs activated in vivo downregulate cross-presentation.
Figure 2: Activation of DCs in vivo impairs cross-priming.
Figure 3: Activation stimuli downregulate the phagocytic activity of DCs in vivo.
Figure 4: Impaired antiviral responses in mice pretreated with TLR ligands.
Figure 5: Impaired presentation of HSV antigens in the lymph node of CpG-treated mice in a zosteriform model of infection.
Figure 6: Impairment of endogenous anti-HSV CTL responses in CpG-treated mice.
Figure 7: P. berghei infection causes systemic DC activation and downregulates cross-presentation.
Figure 8: Impaired cross-presentation in P. berghei-infected mice.

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Acknowledgements

We thank L. Buckingham, K. Gray, D. John, C. Jordan, F. Kupresanin, J. Langley, J.-L. Tan and all members of the Flow Cytometry and the Animal Services facilities at the Walter and Eliza Hall Institute for technical assistance. Supported by the National Health and Medical Research Council of Australia (G.T.B., F.R.C., K.S., B.S.C., W.R.H. and J.A.V.), the Anti-Cancer Council of Australia (J.A.V.), the Deutsche Forschungsgemeinschaft BE 2089/1-1 (G.M.N.B.), the Wellcome Trust (G.T.B.), Howard Hughes Medical Institute (G.T.B., B.S.C. and W.R.H.) and the Leukemia and Lymphoma Society (J.A.V.).

Author information

Author notes

  1. Nicholas S Wilson

    Present address: CSL, Parkville, Victoria, 3052, Australia

  2. Georg M N Behrens

    Present address: Division of Clinical Immunology, Hannover Medical School, Hannover, 3623, Germany

  3. Nicholas S Wilson, Georg M N Behrens and Rachel J Lundie: These authors contributed equally to this work.

Authors and Affiliations

  1. The Walter and Eliza Hall Institute of Medical Research, Parkville, 3050, Victoria, Australia

    Nicholas S Wilson, Georg M N Behrens, Rachel J Lundie, Christopher M Smith, Louise Young, Simon P Forehan, Adele Mount, Ken D Shortman, Tania F de Koning-Ward, Gabrielle T Belz, Brendan S Crabb, William R Heath & Jose A Villadangos

  2. The Cooperative Research Centre for Vaccine Technology, Parkville, 3050, Victoria, Australia

    Nicholas S Wilson, Rachel J Lundie, Christopher M Smith, Ken D Shortman, Gabrielle T Belz, Francis R Carbone, Brendan S Crabb, William R Heath & Jose A Villadangos

  3. Department of Medical Biology Immunology, University of Melbourne, Parkville, 3010, Victoria, Australia

    Nicholas S Wilson, Rachel J Lundie, Christopher M Smith, Louise Young, Simon P Forehan & Adele Mount

  4. Department of Microbiology and Immunology, University of Melbourne, Parkville, 3010, Victoria, Australia

    Jason Waithman & Francis R Carbone

  5. The Centre for Immunology and Cancer Research, The University of Queensland, Woolloongabba, 4102, Queensland, Australia

    Raymond J Steptoe

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Supplementary information

Supplementary Fig. 1

Maturation of lymphoid organ resident DC in TLR ligand-injected mice. (PDF 53 kb)

Supplementary Fig. 2

Down-regulation of MHC II presentation of cell-associated OVA in TLR ligand-treated mice. (PDF 31 kb)

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Wilson, N., Behrens, G., Lundie, R. et al. Systemic activation of dendritic cells by Toll-like receptor ligands or malaria infection impairs cross-presentation and antiviral immunity. Nat Immunol 7, 165–172 (2006). https://doi.org/10.1038/ni1300

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