Type I interferon signaling contributes to the bias that Toll-like receptor 4 exhibits for signaling mediated by the adaptor protein TRIF.
Signaling by Toll-like receptor 4 (TLR4) is mediated by either of two adaptor proteins: myeloid differentiation marker 88 (MyD88) or Toll-interleukin-1 (IL-1) receptor (TIR) domain-containing adaptor inducing interferon-β (TRIF). Whereas MyD88-mediated signaling leads to proinflammatory responses, TRIF-mediated signaling leads to less toxic immunostimulatory responses that are beneficial in boosting vaccine responses. The hypothesis that monophosphorylated lipid A structures act as TRIF-biased agonists of TLR4 offered a potential mechanism to explain their clinical value as vaccine adjuvants, but studies of TRIF-biased agonists have been contradictory. In experiments with mouse dendritic cells, we found that irrespective of the agonist used, TLR4 functioned as a TRIF-biased signaling system through a mechanism that depended on the autocrine and paracrine effects of type I interferons. The TLR4 agonist synthetic lipid A induced expression of TRIF-dependent genes at lower concentrations than were necessary to induce the expression of genes that depend on MyD88-mediated signaling. Blockade of type I interferon signaling selectively decreased the potency of lipid A (increased the concentration required) in inducing the expression of TRIF-dependent genes, thereby eliminating adaptor bias. These data may explain how high-potency TLR4 agonists can act as clinically useful vaccine adjuvants by selectively activating TRIF-dependent signaling events required for immunostimulation, without or only weakly activating potentially harmful MyD88-dependent inflammatory responses.
Department of Microbiology and Immunology, University of Louisville School of Medicine, 570 South Preston Street, Louisville, KY 40202, USA. Institute for Cellular Therapeutics, University of Louisville School of Medicine, Louisville, KY 40202, USA.
Joseph P
JP
Kolb
Institute for Cellular Therapeutics, University of Louisville School of Medicine, Louisville, KY 40202, USA.
Carolyn R
CR
Casella
Department of Microbiology and Immunology, University of Louisville School of Medicine, 570 South Preston Street, Louisville, KY 40202, USA. Institute for Cellular Therapeutics, University of Louisville School of Medicine, Louisville, KY 40202, USA.
Shuvasree
S
SenGupta
Department of Microbiology and Immunology, University of Louisville School of Medicine, 570 South Preston Street, Louisville, KY 40202, USA. Institute for Cellular Therapeutics, University of Louisville School of Medicine, Louisville, KY 40202, USA.
Paula M
PM
Chilton
Department of Microbiology and Immunology, University of Louisville School of Medicine, 570 South Preston Street, Louisville, KY 40202, USA. Institute for Cellular Therapeutics, University of Louisville School of Medicine, Louisville, KY 40202, USA. tom.mitchell@louisville.edu.
Thomas C
TC
Mitchell
D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism*; D000818:Animals; D018122:B7-1 Antigen / Q000378:metabolism; D051940:B7-2 Antigen / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000166:cytology; D005786:Gene Expression Regulation; D007249:Inflammation; D007370:Interferon Type I / Q000378:metabolism*; D016899:Interferon-beta / Q000378:metabolism; D008050:Lipid A / Q000737:chemistry*; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism*; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000378:metabolism*
D033942:Adaptor Proteins, Vesicular Transport; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D016207:Cytokines; D007370:Interferon Type I; D016899:Interferon-beta; D008050:Lipid A; D048670:MAP Kinase Kinase 4; D053594:Myeloid Differentiation Factor 88; D051197:Toll-Like Receptor 4; C497965:Cd86 protein, mouse; C507780:Myd88 protein, mouse; C476286:Ticam1 protein, mouse; C493487:Tlr4 protein, mouse