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首页> 外文期刊>Vaccine >Enhancing the potency of peptide-pulsed antigen presenting cells by vector-driven hyperexpression of a triad of costimulatory molecules
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Enhancing the potency of peptide-pulsed antigen presenting cells by vector-driven hyperexpression of a triad of costimulatory molecules

机译：通过载体驱动的三刺激共刺激分子增强肽脉冲抗原呈递细胞的效力

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Recombinant orthopox vectors (both replication-defective fowlpox [rF]. and replication competent vaccinia [rV] have been developed that simultaneously express three T-cell costimulatory molecule transgenes. The constituents of this, triad of costimulatory molecules (designated TRICOM) are B7-1, ICAM-1, and LFA-3. We have previously shown that infection of murine dendritic cells (DCs) with TRICOM vectors increases their level of expression of the triad of costimulatory molecules and enhances the efficacy of DCs to activate T cells. While DCs are arguably the most potent antigen presenting cell (APC), limitations clearly exist in their use due to the level of effort and cost for their generation. The studies reported here demonstrate that a generic APC population, murine splenocytes, can be made markedly more efficient as APCs by infection with either rF-TRICOM or rV-TRICOM vectors. Infection of splenocytes with either TRICOM vector led to significant improvement of APC capabilities in terms of: (a) enhancement of mixed lymphocyte reactions, (b) a reduction in the amount of signal 1 to activate naive T cells; and (c) a reduction in the amount of APCs required to activate T cells using a constant amount of signal 1. TRICOM-enhanced T-cell activation was shown to correspond to increases in type-1 cytokines and a reduced level of apoptosis. compared with T cells activated with uninfected or control vector-infected splenocytes. In vitro and in vivo experiments compared DCs with TRICOM-infected splenocytes. Infection of splenocytes with TRICOM vectors markedly enhanced their ability to activate T cells to levels approaching that of DCs. These studies thus demonstrate for the first time that an abundant and accessible population of APCs obtainable without lengthy culture or the use of costly exogenous cytokines tin contrast to that of DCs) can be made more potent as APCs with the use of vectors that express a triad of costimulatory molecules.
机译：已经开发了同时表达三个T细胞共刺激分子转基因的重组正痘载体（复制缺陷型禽痘[rF]。和复制能力牛痘[rV]）。这组共刺激分子三联体（称为TRICOM）是B7- 1，ICAM-1和LFA-3。我们先前已经证明，用TRICOM载体感染鼠树突状细胞（DC）可以提高共刺激分子三联体的表达水平，并增强DC激活T细胞的功效。 DCs可以说是最有效的抗原呈递细胞（APC），由于其努力水平和生成成本的缘故，其使用上显然存在局限性，此处报道的研究表明，可以显着地制造出更多的APC通用种群，即鼠脾细胞。通过用rF-TRICOM或rV-TRICOM载体感染可有效作为APC。用TRICOM载体感染脾细胞可显着改善APC的功能（a）增强混合淋巴细胞反应，（b）减少激活幼稚T细胞的信号1的量; （c）使用恒定量的信号1激活T细胞所需的APC数量减少。显示TRICOM增强的T细胞激活与1型细胞因子增加和凋亡水平降低相对应。与未感染或对照载体感染的脾细胞激活的T细胞相比。体外和体内实验将DC与TRICOM感染的脾细胞进行了比较。用TRICOM载体感染脾细胞显着增强了它们激活T细胞的能力，使其水平接近DC。因此，这些研究首次证明，无需长时间培养或使用昂贵的外源细胞因子（与DC相比，无需使用昂贵的外源细胞因子即可获得）的APC群体可以更有效地作为APC使用表达三联体的载体共刺激分子。

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