Toll-like receptor 3 promotes cross-priming to virus-infected cells.
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). 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 material. 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 CD8alpha+ 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.
Schulz
Oliver
O
Immunobiology Laboratory, Cancer Research UK London Research Institute, Lincoln's Inn Fields Laboratories, 44 Lincoln's Inn Fields, London WC2A 3PX, UK.
Diebold
Sandra S
SS
Chen
Margaret
M
Näslund
Tanja I
TI
Nolte
Martijn A
MA
Alexopoulou
Lena
L
Azuma
Yasu-Taka
YT
Flavell
Richard A
RA
Liljeström
Peter
P
Reis e Sousa
Caetano
C
D000818:Animals; D017951:Antigen Presentation / Q000276:immunology*; D018188:Cardiovirus Infections / Q000276:immunology*; D002522:Chlorocebus aethiops; D045142:Cross-Priming / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology; D004686:Encephalomyocarditis virus / Q000276:immunology / Q000502:physiology; D011992:Endosomes / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D010047:Ovalbumin / Q000276:immunology; D011070:Poly I-C / Q000276:immunology / Q000378:metabolism; D012330:RNA, Double-Stranded / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D051196:Toll-Like Receptor 3; D051193:Toll-Like Receptors; D014709:Vero Cells
D008562:Membrane Glycoproteins; D012330:RNA, Double-Stranded; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D051196:Toll-Like Receptor 3; D051193:Toll-Like Receptors; D010047:Ovalbumin; D011070:Poly I-C