Targeting antigen to MHC class I and class II antigen presentation pathways for malaria DNA vaccines
Targeting antigen to MHC class I and class II antigen presentation pathways for malaria DNA vaccines
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DOI：
10.1016/j.imlet.2007.05.007
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发表时间：
2007-08-15
影响因子：
4.4
通讯作者：
Doolan, Denise L.
中科院分区：
文献类型：
--
作者：
Dobano, Carlota;Rogers, William O.;Doolan, Denise L.
一种有效的疟疾疫苗，保护免受疟原虫感染的所有阶段，可能需要引发强大的CD 8（+）和CD 4（+）T细胞和抗体反应。为了实现这一目标，我们已经研究了旨在提高编码约氏疟原虫红细胞前阶段抗原PyCSP和PyHEP 17的DNA疫苗的免疫原性的策略，通过将编码的蛋白质靶向MHC I类和II类加工和呈递途径。为了增强CD 8（+）T细胞的应答，我们根据N-末端规则通过泛素（Ub）/蛋白体途径靶向抗原进行降解。我们构建了含有与Ub基因融合的PyCSP或PyHEP 17基因的质粒：其中N-末端抗原残基从稳定氨基酸甲硫氨酸突变为不稳定精氨酸的质粒，其中Ub的C-末端残基从甘氨酸突变为丙氨酸的质粒，以及其中抗原的潜在疏水前导序列缺失的质粒。为了增强CD 4（+）T细胞和抗体应答，我们通过将抗原连接到溶酶体相关膜蛋白（LAMP）来靶向抗原以通过内体/溶酶体途径降解。我们发现，与未修饰的疫苗相比，用编码PyHEP 17融合至Ub并携带精氨酸的DNA疫苗免疫诱导更高的IFN-γ、细胞毒性和增殖性T细胞应答。然而，对于使用相同靶向策略的PyCSP没有观察到效果。关于II类抗原靶向，与LAMP的融合不增强对PyHEP 17或PyCSP的抗体应答，并且导致淋巴增生性CD 4（+）T细胞应答的轻微增加。我们的数据突出了免疫增强策略的抗原依赖性，该策略将抗原靶向至用于疫苗开发的MHC I类和II类途径。(c)2007 Elsevier B. V.保留所有权利。
An effective malaria vaccine which protects against all stages of Plasmodium infection may need to elicit robust CD8(+) and CD4(+) T cell and antibody responses. To achieve this, we have investigated strategies designed to improve the immunogenicity of DNA vaccines encoding the Plasmodium yoelii pre-erythrocytic stage antigens PyCSP and PyHEP17, by targeting the encoded proteins to the MHC Classes I and II processing and presentation pathways. For enhancement of CD8(+) T cell responses, we targeted the antigens for degradation by the ubiquitin (Ub)/proteosome pathway following the N-terminal rule. We constructed plasmids containing PyCSP or PyHEP17 genes fused to the Ub gene: plasmids where the N-terminal antigen residues were mutated from the stabilizing amino acid methionine to destabilizing arginine, plasmids where the C-terminal residues of Ub were mutated from glycine to alanine, and plasmids in which the potential hydrophobic leader sequences of the antigens were deleted. For enhancement of CD4(+) T cell and antibody responses, we targeted the antigens for degradation by the endosomal/lysosomal pathway by linking the antigen to the lysosome-associated membrane protein (LAMP). We found that immunization with DNA vaccine encoding PyHEP17 fused to Ub and bearing arginine induced higher IFN-gamma, cytotoxic and proliferative T cell responses than unmodified vaccines. However, no effect was seen for PyCSP using the same targeting strategies. Regarding Class II antigen targeting, fusion to LAMP did not enhance antibody responses to either PyHEP17 or PyCSP, and resulted in a marginal increase in lymphoproliferative CD4(+) T cell responses. Our data highlight the antigen dependence of immune enhancement strategies that target antigen to the MHC Class I and II pathways for vaccine development. (c) 2007 Elsevier B.V. All rights reserved.