Systemic activation of dendritic cells by Toll-like receptor ligands or malaria infection impairs cross-presentation and antiviral immunity.
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.
Wilson
Nicholas S
NS
The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3050, Australia.
Behrens
Georg M N
GM
Lundie
Rachel J
RJ
Smith
Christopher M
CM
Waithman
Jason
J
Young
Louise
L
Forehan
Simon P
SP
Mount
Adele
A
Steptoe
Raymond J
RJ
Shortman
Ken D
KD
de Koning-Ward
Tania F
TF
Belz
Gabrielle T
GT
Carbone
Francis R
FR
Crabb
Brendan S
BS
Heath
William R
WR
Villadangos
Jose A
JA
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*
D000956:Antigens, Viral; D008024:Ligands; D051193:Toll-Like Receptors; D010047:Ovalbumin