A TLR4 agonist synergizes with dendritic cell-directed lentiviral vectors for inducing antigen-specific immune responses.
TLR4 agonists can be used as adjuvants to trigger innate immune responses of antigen-presenting cells (APCs) such as dendritic cells (DCs) to enhance vaccine-specific immunity. Adjuvant effects of TLR4 agonists are mediated by downstream signaling controlled by both MyD88 and TRIF adapter proteins. In this study, we investigated the adjuvanting capacity of glucopyranosyl lipid A (GLA), a chemically synthesized TLR4 agonist, to boost antigen-specific immunity elicited by DC-directed lentiviral vectors (DC-LV). We found that stimulation by this agonist in vitro can activate DCs in a TLR4-dependent manner. The agonist can significantly boost DC-LV-induced humoral and cellular immune responses, resulting in better antitumor reactions in response to tumor challenges. We observed that the adjuvant-mediated enhancement of cytotoxic CD8(+) T cell responses is CD4(+) T cell-dependent and determined that in vitro the agonist stimulation involves the participation of both MyD88 and TRIF pathways to activate DCs. In vivo immunization study however revealed that adjuvant effects depend more on the MyD88 signaling as TRIF(-/-) mice but not MyD88(-/-) mice were able to maintain the enhanced CD8(+) T cell responses upon DC-LV immunization. Thus, our study supports the use of this TLR4 agonist as a potent adjuvant candidate for boosting DC-LV immunization.
Mork Family Department of Chemical Engineering and Materials Science, University of Southern California, Los Angeles, CA 90089, USA.
Liang
L
Xiao
Jocelyn
J
Kim
Matthew
M
Lim
Bingbing
B
Dai
Lili
L
Yang
Steven G
SG
Reed
David
D
Baltimore
Pin
P
Wang
D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000378:metabolism; D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology*; D005260:Female; D005822:Genetic Vectors; D056724:Immunity, Humoral / Q000187:drug effects / Q000276:immunology; D016086:Lentivirus / Q000235:genetics*; D008050:Lipid A / Q000031:analogs & derivatives / Q000494:pharmacology*; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000819:agonists*
D033942:Adaptor Proteins, Vesicular Transport; D000276:Adjuvants, Immunologic; D008050:Lipid A; D053594:Myeloid Differentiation Factor 88; D051197:Toll-Like Receptor 4; C476286:Ticam1 protein, mouse