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

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• 作者：Liang Xiao^a ; Jocelyn Kim^b ; Matthew Lim^a ; Bingbing Dai^a ; Lili Yang^b ; Steven G. Reed^c ; David Baltimore^b ; ^{baltimo@caltech.edu} ; Pin Wang^a ; ^d ; ^e ; ^{pinwang@usc.edu}
• 关键词：LV ; lentiviral vector ; DC ; dendritic cells ; GLA ; glucopyranosyl lipid A ; MPL ; monophosphoryl lipid A ; OVA ; ovalbumin ; TLR ; Toll-like receptor ; MHC ; major histocompatibility complex ; APC ; antigen-presenting cells ; BMDC ; bone marrow-derived dendritic cell
• 刊名：Vaccine
• 出版年：2012
• 期刊代码：89_0264410x
• 类别：imm
• 出版时间：28 March, 2012
• 卷：30
• 期：15
• 页码：2570-2581
• 文件大小：1690 K

摘要

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^{鈭?鈭?/sup> mice but not MyD88鈭?鈭?/sup> 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.}