Nontoxic Shiga Toxin Derivatives from Escherichia coli Possess Adjuvant Activity for the Augmentation of Antigen-Specific Immune Responses via Dendritic Cell Activation
Nontoxic Shiga Toxin Derivatives from Escherichia coli Possess Adjuvant Activity for the Augmentation of Antigen-Specific Immune Responses via Dendritic Cell Activation
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DOI：
10.1128/iai.73.7.4088-4097.2005
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发表时间：
2005-07
影响因子：
3.1
通讯作者：
M. Ohmura;Masafumi Yamamoto;C. Tomiyama-Miyaji;Y. Yuki;Y. Takeda;H. Kiyono
中科院分区：
文献类型：
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作者：
M. Ohmura;Masafumi Yamamoto;C. Tomiyama-Miyaji;Y. Yuki;Y. Takeda;H. Kiyono
志贺滋贺衍生物，如介导毒素与细胞膜结合的Stx 1 B亚基（StxB 1）和突变型Stx 1（mStx 1），其是一种无毒的双突变Stx 1，在A亚基中含有氨基酸取代，通过激活树突状细胞（DCs）而具有佐剂活性。我们的研究结果表明，StxB 1和mStx 1，而不是天然Stx 1（nStx 1），导致CD 86，CD 40和主要组织相容性复合物（MHC）II类分子的表达增强，并在一定程度上，也增强了CD 80的表达骨髓来源的DC。StxB 1处理的DC表现出肿瘤坏死因子α和白细胞介素-12（IL-12）产生的增加，DO11.10 T细胞增殖的刺激，以及Th 1和Th 2细胞因子（包括γ干扰素（IFN-γ）、IL-4、IL-5、IL-6和IL-10）的产生。当小鼠皮下给予StxB 1时，CD 80，CD 86和CD 40的水平以及脾脏DCs的MHC II类表达均增强。用卵清蛋白（OVA）加mStx 1或StxB 1皮下免疫小鼠诱导血清中高滴度的OVA特异性免疫球蛋白M（IgM）、IgG 1和IgG 2a。从用OVA加mStx 1或StxB 1免疫的小鼠中分离的OVA特异性CD 4 + T细胞产生IFN-γ、IL-4、IL-5、IL-6和IL-10，表明mStx 1和StxB 1引起Th 1型和Th 2型应答。重要的是，用破伤风类毒素加mStx 1或StxB 1皮下免疫的小鼠受到破伤风毒素致死攻击的保护。这些结果表明，无毒的Stx衍生物，包括StxB 1和mStx 1，可以是有效的佐剂诱导混合Th型CD 4 + T细胞介导的抗原特异性抗体反应，通过激活的DC。
ABSTRACT Shiga toxin (Stx) derivatives, such as the Stx1 B subunit (StxB1), which mediates toxin binding to the membrane, and mutant Stx1 (mStx1), which is a nontoxic doubly mutated Stx1 harboring amino acid substitutions in the A subunit, possess adjuvant activity via the activation of dendritic cells (DCs). Our results showed that StxB1 and mStx1, but not native Stx1 (nStx1), resulted in enhanced expression of CD86, CD40, and major histocompatibility complex (MHC) class II molecules and, to some extent, also enhanced the expression of CD80 on bone marrow-derived DCs. StxB1-treated DCs exhibited an increase in tumor necrosis factor alpha and interleukin-12 (IL-12) production, a stimulation of DO11.10 T-cell proliferation, and the production of both Th1 and Th2 cytokines, including gamma interferon (IFN-γ), IL-4, IL-5, IL-6, and IL-10. When mice were given StxB1 subcutaneously, the levels of CD80, CD86, and CD40, as well as MHC class II expression by splenic DCs, were enhanced. The subcutaneous immunization of mice with ovalbumin (OVA) plus mStx1 or StxB1 induced high titers of OVA-specific immunoglobulin M (IgM), IgG1, and IgG2a in serum. OVA-specific CD4+ T cells isolated from mice immunized with OVA plus mStx1 or StxB1 produced IFN-γ, IL-4, IL-5, IL-6, and IL-10, indicating that mStx1 and StxB1 elicit both Th1- and Th2-type responses. Importantly, mice immunized subcutaneously with tetanus toxoid plus mStx1 or StxB1 were protected from a lethal challenge with tetanus toxin. These results suggest that nontoxic Stx derivatives, including both StxB1 and mStx1, could be effective adjuvants for the induction of mixed Th-type CD4+ T-cell-mediated antigen-specific antibody responses via the activation of DCs.