Systemic administration of a TLR7 ligand leads to transient immune incompetence due to peripheral-blood leukocyte depletion

• Published in: Blood 2005-10, Vol.106 (7), p.2424-2432
• Main Authors: Gunzer, Matthias, Riemann, Helge, Basoglu, Yasmin, Hillmer, Anja, Weishaupt, Carsten, Balkow, Sandra, Benninghoff, Bernd, Ernst, Beat, Steinert, Meike, Scholzen, Thomas, Sunderkötter, Cord, Grabbe, Stephan
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing - metabolism; Animals; Antigens, Differentiation - metabolism; Biological and medical sciences; CD4-Positive T-Lymphocytes - cytology; CD8-Positive T-Lymphocytes - cytology; Cell Adhesion; Dermatitis, Contact; Endothelium, Vascular - cytology; Endothelium, Vascular - metabolism; Female; Imidazoles - pharmacology; Immune System - drug effects; Immunohistochemistry; Immunopathology; Immunotherapy (general aspects); Leukocyte Rolling; Leukocytes - cytology; Leukocytes - drug effects; Leukocytes, Mononuclear - metabolism; Ligands; Medical sciences; Membrane Glycoproteins - metabolism; Mice; Mice, Inbred BALB C; Microscopy, Fluorescence; Myeloid Differentiation Factor 88; Receptors, Immunologic - metabolism; Selectins - metabolism; Signal Transduction; Time Factors; Toll-Like Receptor 7 - metabolism; Up-Regulation
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2005-01-0342

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. (Blood. 2005;106:2424-2432)