Internalization and coreceptor expression are critical for TLR2-mediated recognition of lipoteichoic acid in human peripheral blood.
Lipoteichoic acid (LTA), a ubiquitous cell wall component of Gram-positive bacteria, represents a potent immunostimulatory molecule. Because LTA of a mutant Staphylococcus aureus strain lacking lipoproteins (Deltalgt-LTA) has been described to be immunobiologically inactive despite a lack of ascertained structural differences to wild-type LTA (wt-LTA), we investigated the functional requirements for the recognition of Deltalgt-LTA by human peripheral blood cells. In this study, we demonstrate that Deltalgt-LTA-induced immune activation critically depends on the immobilization of LTA and the presence of human serum components, which, to a lesser degree, was also observed for wt-LTA. Under experimental conditions allowing LTA-mediated stimulation, we found no differences between the immunostimulatory capacity of Deltalgt-LTA and wt-LTA in human blood cells, arguing for a limited contribution of possible lipoprotein contaminants to wt-LTA-mediated immune activation. In contrast to human blood cells, TLR2-transfected human embryonic kidney 293 cells could be activated only by wt-LTA, whereas activation of these cells by Deltalgt-LTA required the additional expression of TLR6 and CD14, suggesting that activation of human embryonic kidney 293 cells expressing solely TLR2 is probably mediated by residual lipoproteins in wt-LTA. Notably, in human peripheral blood, LTA-specific IgG Abs are essential for Deltalgt-LTA-mediated immune activation and appear to induce the phagocytic uptake of Deltalgt-LTA via engagement of FcgammaRII. In this study, we have elucidated a novel mechanism of LTA-induced cytokine induction in human peripheral blood cells that involves uptake of LTA and subsequent intracellular recognition driven by TLR2, TLR6, and CD14.
Bunk
Sebastian
S
Department of Biochemical Pharmacology, University of Konstanz, Konstanz, Germany. sebastian.bunk@gmx.net
Sigel
Stefanie
S
Metzdorf
Daniela
D
Sharif
Omar
O
Triantafilou
Kathy
K
Triantafilou
Martha
M
Hartung
Thomas
T
Knapp
Sylvia
S
von Aulock
Sonja
S
D000276:Adjuvants, Immunologic / Q000097:blood* / Q000235:genetics / Q000502:physiology; D000937:Antigen-Antibody Reactions; D002460:Cell Line; D002462:Cell Membrane / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D016207:Cytokines / Q000096:biosynthesis / Q000097:blood / Q000378:metabolism; D006801:Humans; D007074:Immunoglobulin G / Q000378:metabolism; D007424:Intracellular Fluid / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D018950:Lipopolysaccharide Receptors / Q000096:biosynthesis / Q000502:physiology; D008070:Lipopolysaccharides / Q000097:blood / Q000276:immunology / Q000378:metabolism*; D008074:Lipoproteins / Q000172:deficiency / Q000235:genetics; D009895:Opsonin Proteins / Q000378:metabolism; D017452:Receptors, IgG / Q000502:physiology; D013211:Staphylococcus aureus / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D013682:Teichoic Acids / Q000097:blood / Q000276:immunology / Q000378:metabolism*; D051195:Toll-Like Receptor 2 / Q000097:blood / Q000378:metabolism* / Q000502:physiology; D051216:Toll-Like Receptor 6 / Q000096:biosynthesis / Q000502:physiology
D000276:Adjuvants, Immunologic; D016207:Cytokines; C080568:Fc gamma receptor IIA; D007074:Immunoglobulin G; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D008074:Lipoproteins; D009895:Opsonin Proteins; D017452:Receptors, IgG; C495342:TLR2 protein, human; C495368:TLR6 protein, human; D013682:Teichoic Acids; D051195:Toll-Like Receptor 2; D051216:Toll-Like Receptor 6; C009900:lipoteichoic acid