Systemic administration of a TLR7 ligand leads to transient immune incompetence due to peripheral-blood leukocyte depletion.
Toll-like receptor (TLR) ligands lead to the induction of proinflammatory cytokines and are potent enhancers of specific immune responses. We show here that a single systemic dose of R-848, a ligand for TLR7, potently enhanced hapten sensitization during the induction of contact hypersensitivity (CHS). However, R-848 administration also resulted in a rapid and almost complete depletion of leukocytes from the blood. This effect was transient and was associated with general induction of endothelial adhesiveness. In response to R-848, endothelial cells up-regulated adhesion molecules in vitro and in vivo and leukocytes exhibited increased rolling on endothelia in R-848-treated animals. Adhesion molecule induction appeared to be a direct effect, because endothelial cells expressed TLR7 in vitro and in vivo. After R-848 treatment, the tissue residence time of leukocytes was markedly prolonged in all major peripheral organs. The resulting transiently reduced availability of peripheral-blood leukocytes (PBLs) (TRAP) significantly inhibited otherwise potent CHS responses until the effector cells returned. Thus, although TLR7 ligands are effective adjuvants for the induction of cell-mediated immunity, they can transiently inhibit the elicitation of localized immune responses, possibly due to a systemic endothelial activation throughout the vasculature.
German Research Centre for Biotechnology, Junior Research Group Immunodynamics, Braunschweig, Germany. mgunzer@gbf.de
Matthias
M
Gunzer
Helge
H
Riemann
Yasmin
Y
Basoglu
Anja
A
Hillmer
Carsten
C
Weishaupt
Sandra
S
Balkow
Bernd
B
Benninghoff
Beat
B
Ernst
Meike
M
Steinert
Thomas
T
Scholzen
Cord
C
Sunderkötter
Stephan
S
Grabbe
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D000943:Antigens, Differentiation / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology; D002448:Cell Adhesion; D003877:Dermatitis, Contact; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D005260:Female; D007093:Imidazoles / Q000494:pharmacology; D007107:Immune System / Q000187:drug effects*; D007150:Immunohistochemistry; D036904:Leukocyte Rolling; D007962:Leukocytes / Q000166:cytology / Q000187:drug effects*; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008024:Ligands; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008856:Microscopy, Fluorescence; D053594:Myeloid Differentiation Factor 88; D011971:Receptors, Immunologic / Q000378:metabolism; D019087:Selectins / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D051199:Toll-Like Receptor 7 / Q000378:metabolism*; D015854:Up-Regulation
D048868:Adaptor Proteins, Signal Transducing; D000943:Antigens, Differentiation; D007093:Imidazoles; D008024:Ligands; D008562:Membrane Glycoproteins; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D011971:Receptors, Immunologic; D019087:Selectins; C477038:Tlr7 protein, mouse; D051199:Toll-Like Receptor 7; C402365:resiquimod