Nature Immunology 7, 165 - 172 (2006)
Published online: 15 January 2006; | doi:10.1038/ni1300
Systemic activation of dendritic cells by Toll-like receptor ligands or malaria infection impairs cross-presentation and antiviral immunityNicholas S Wilson1, 2, 3, 6, 7, Georg M N Behrens1, 6, 7, Rachel J Lundie1, 2, 3, 7, Christopher M Smith1, 2, 3, Jason Waithman4, Louise Young1, 3, Simon P Forehan1, 3, Adele Mount1, 3, Raymond J Steptoe5, Ken D Shortman1, 2, Tania F de Koning-Ward1, Gabrielle T Belz1, 2, Francis R Carbone2, 4, Brendan S Crabb1, 2, William R Heath1, 2
& Jose A Villadangos1, 21
The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3050, Australia. 2
The Cooperative Research Centre for Vaccine Technology, Parkville, Victoria 3050, Australia. 3
Department of Medical Biology Immunology, University of Melbourne, Parkville, Victoria 3010, Australia. 4
Department of Microbiology and Immunology, University of Melbourne, Parkville, Victoria 3010, Australia. 5
The Centre for Immunology and Cancer Research, The University of Queensland, Woolloongabba, Queensland 4102, Australia. 6
Present addresses: CSL, Parkville, Victoria 3052, Australia (N.S.W.), and Division of Clinical Immunology, Hannover Medical School, Hannover 3623, Germany (G.M.N.B.). 7
These authors contributed equally to this work.
Correspondence should be addressed to Brendan S Crabb crabb@wehi.edu.au or William R Heath heath@wehi.edu.au or Jose A Villadangos villadangos@wehi.edu.au 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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