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A TLR4 agonist synergizes with dendritic cell-directed lentiviral vectors for inducing antigen-specific immune responses

Xiao, Liang and Kim, Jocelyn and Lim, Matthew and Dai, Bingbing and Yang, Lili and Reed, Steven G. and Baltimore, David and Wang, Pin (2012) A TLR4 agonist synergizes with dendritic cell-directed lentiviral vectors for inducing antigen-specific immune responses. Vaccine, 30 (15). pp. 2570-2581. ISSN 0264-410X. http://resolver.caltech.edu/CaltechAUTHORS:20120508-105234824

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Abstract

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.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1016/j.vaccine.2012.01.074DOIUNSPECIFIED
http://www.sciencedirect.com/science/article/pii/S0264410X12001120PublisherUNSPECIFIED
ORCID:
AuthorORCID
Kim, Jocelyn0000-0001-8723-8190
Baltimore, David0000-0001-8723-8190
Additional Information:© 2012 Elsevier Ltd. Received 13 December 2011; Received in revised form 24 January 2012; Accepted 24 January 2012; Available online 5 February 2012. We thank Paul Bryson and April Tai for critical reading of the manuscript. This work was supported by grants from the National Institutes of Health (R01AI68978 and P01CA132681), a grant from the Bill and Melinda Gates Foundation, a translational acceleration grant from the Joint Center for Translational Medicine and a grant from the California HIV/AIDS Research Program.
Funders:
Funding AgencyGrant Number
NIHR01AI68978
NIHP01CA132681
Bill and Melinda Gates FoundationUNSPECIFIED
Joint Center for Translational MedicineUNSPECIFIED
California HIV/AIDS Research ProgramUNSPECIFIED
Subject Keywords:Adjuvant; TLR4 agonist; Dendritic cells; MyD88; TRIF; Lentiviral vector
Record Number:CaltechAUTHORS:20120508-105234824
Persistent URL:http://resolver.caltech.edu/CaltechAUTHORS:20120508-105234824
Official Citation:Liang Xiao, Jocelyn Kim, Matthew Lim, Bingbing Dai, Lili Yang, Steven G. Reed, David Baltimore, Pin Wang, A TLR4 agonist synergizes with dendritic cell-directed lentiviral vectors for inducing antigen-specific immune responses, Vaccine, Volume 30, Issue 15, 28 March 2012, Pages 2570-2581, ISSN 0264-410X, 10.1016/j.vaccine.2012.01.074.
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:31350
Collection:CaltechAUTHORS
Deposited By: Jason Perez
Deposited On:08 May 2012 18:36
Last Modified:09 Nov 2017 00:27

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