Encryption of agonistic motifs for TLR4 into artificial antigens augmented the maturation of antigen-presenting cells.
Encryption of agonistic motifs for TLR4 into artificial antigens augmented the maturation of antigen-presenting cells.
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DOI：
10.1371/journal.pone.0188934
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Shiba K
中科院分区：
文献类型：
--
作者：
Ito M;Hayashi K;Minamisawa T;Homma S;Koido S;Shiba K
佐剂对于从疫苗接种中获得足够的免疫应答是必不可少的。从功能的角度来看，佐剂分为两类：“物理佐剂”增加抗原呈递细胞（APC）的抗原呈递效率和“信号佐剂”诱导APC的成熟。我们先前的研究已经证明，通过从表位肽和具有形成某些蛋白质结构的倾向的那些肽序列的组合物产生人工蛋白质（基序编程），可以将物理佐剂加密成蛋白质抗原。然而，人工抗原仍然需要信号佐剂来使APC成熟;例如，需要共同施用Toll样受体4（TLR 4）激动剂单磷酰脂质A（MPLA）来诱导体内免疫反应。在这项研究中，我们进一步修改了以前的人工抗原，通过附加的肽基序，这已被报道具有激动活性的TLR 4，以创建“无佐剂”抗原。在其C-末端具有三重TLR 4激动基序的所产生的抗原具有通过TLR 4激活的NF-κB信号传导途径。这些蛋白还诱导炎性细胞因子TNF-α的产生，以及APC中共刺激分子CD 40的表达，支持APC在体外的成熟。出乎意料的是，这些信号传导剂加密的蛋白失去了它们作为物理佐剂的能力，因为它们在体内不诱导细胞毒性T淋巴细胞（CTL），而亲本蛋白诱导CTL。这些结果证实了模体功能的表现是依赖于上下文的，简单的加法并不总是适用于模体编程。应需要进一步优化抗原中TLR 4激动性基序的分子背景以产生无促凝剂的抗原。
Adjuvants are indispensable for achieving a sufficient immune response from vaccinations. From a functional viewpoint, adjuvants are classified into two categories: “physical adjuvants” increase the efficacy of antigen presentation by antigen-presenting cells (APC) and “signal adjuvants” induce the maturation of APC. Our previous study has demonstrated that a physical adjuvant can be encrypted into proteinous antigens by creating artificial proteins from combinatorial assemblages of epitope peptides and those peptide sequences having propensities to form certain protein structures (motif programming). However, the artificial antigens still require a signal adjuvant to maturate the APC; for example, co-administration of the Toll-like receptor 4 (TLR4) agonist monophosphoryl lipid A (MPLA) was required to induce an in vivo immunoreaction. In this study, we further modified the previous artificial antigens by appending the peptide motifs, which have been reported to have agonistic activity for TLR4, to create “adjuvant-free” antigens. The created antigens with triple TLR4 agonistic motifs in their C-terminus have activated NF-κB signaling pathways through TLR4. These proteins also induced the production of the inflammatory cytokine TNF-α, and the expression of the co-stimulatory molecule CD40 in APC, supporting the maturation of APC in vitro. Unexpectedly, these signal adjuvant-encrypted proteins have lost their ability to be physical adjuvants because they did not induce cytotoxic T lymphocytes (CTL) in vivo, while the parental proteins induced CTL. These results confirmed that the manifestation of a motif’s function is context-dependent and simple addition does not always work for motif-programing. Further optimization of the molecular context of the TLR4 agonistic motifs in antigens should be required to create adjuvant-free antigens.
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影响因子：
7.3
作者：
Awate S;Babiuk LA;Mutwiri G
通讯作者：
Mutwiri G
影响因子：
64.8
作者：
Park, Beom Seok;Song, Dong Hyun;Lee, Jie-Oh
通讯作者：
Lee, Jie-Oh
DOI：
10.1073/pnas.0609671104
发表时间：
2006-12-26
影响因子：
11.1
作者：
Seimon, Tracie A.;Obstfeld, Amrom;Tabas, Ira
通讯作者：
Tabas, Ira
影响因子：
2.9
作者：
Saxena, RK;Vallyathan, V;Lewis, DM
通讯作者：
Lewis, DM
DOI：
10.1007/978-1-4419-1603-7_10
发表时间：
2009-01-01
期刊：
LIPID A IN CANCER THERAPY
影响因子：
--
作者：
Cluff, Christopher W.
通讯作者：
Cluff, Christopher W.