title: Systemic activation of dendritic cells by Toll-like receptor ligands or malaria infection impairs cross-presentation and antiviral immunity.
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.
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3050, Australia.
authors.forename: Nicholas S
authors.initials: NS
authors.lastname: Wilson
authors.forename: Georg M N
authors.initials: GM
authors.lastname: Behrens
authors.forename: Rachel J
authors.initials: RJ
authors.lastname: Lundie
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Smith
authors.forename: Jason
authors.initials: J
authors.lastname: Waithman
authors.forename: Louise
authors.initials: L
authors.lastname: Young
authors.forename: Simon P
authors.initials: SP
authors.lastname: Forehan
authors.forename: Adele
authors.initials: A
authors.lastname: Mount
authors.forename: Raymond J
authors.initials: RJ
authors.lastname: Steptoe
authors.forename: Ken D
authors.initials: KD
authors.lastname: Shortman
authors.forename: Tania F
authors.initials: TF
authors.lastname: de Koning-Ward
authors.forename: Gabrielle T
authors.initials: GT
authors.lastname: Belz
authors.forename: Francis R
authors.initials: FR
authors.lastname: Carbone
authors.forename: Brendan S
authors.initials: BS
authors.lastname: Crabb
authors.forename: William R
authors.initials: WR
authors.lastname: Heath
authors.forename: Jose A
authors.initials: JA
authors.lastname: Villadangos
mesh_terms: D000818:Animals; D017951:Antigen Presentation; D000956:Antigens, Viral; D018899:CpG Islands / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology*; D006561:Herpes Simplex / Q000276:immunology; D018259:Herpesvirus 1, Human / Q000276:immunology; D007108:Immune Tolerance; D066298:In Vitro Techniques; D008024:Ligands; D008288:Malaria / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010047:Ovalbumin / Q000276:immunology; D010962:Plasmodium berghei; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D051193:Toll-Like Receptors / Q000378:metabolism*
chemical_list: D000956:Antigens, Viral; D008024:Ligands; D051193:Toll-Like Receptors; D010047:Ovalbumin