McIntosh Julie D, Manning Kristy, Chokshi Shilpa, Naoumov Nikolai V, Fraser John D, Dunbar P Rod, Taylor John A
School of Biological Sciences and Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland, New Zealand.
Institute of Hepatology, University College London, London, United Kingdom.
PLoS One. 2014 Apr 1;9(4):e93598. doi: 10.1371/journal.pone.0093598. eCollection 2014.
Virus like particles (VLPs) are potent immunogens capable of priming strong protective antibody responses due to their repetitive structural arrangement and affinity for specific B cell receptors. By contrast, T cell responses to VLPs can be weak due to inefficient uptake and processing by antigen presenting cells. We report here a novel strategy for increasing the T cell reactivity of a VLP, the nucleocapsid of hepatitis B virus, through covalent coupling of M1, an engineered form of the Streptococcal superantigen SMEZ2, that binds MHC II with high affinity but lacks its T cell mitogenic capability. M1:HBcAg conjugates bound to dendritic cells and were efficiently endocytosed into late endosomes. Human dendritic cells pulsed with M1:HBcAgs stimulated HBV-specific CD8(+) T cells more effectively than cells pulsed with native capsids indicating that the modified VLP was more effectively cross presented by APCs. Coupling of M1 was also able to induce significantly greater reactivity of human CD4(+) T cells specific for a common T-helper epitope. These studies indicate the potential of recombinant superantigens to act as flexible molecular adjuvants that can be incorporated into various subunit vaccine platforms leading to enhanced T cell reactivity in humans.
病毒样颗粒（VLPs）是一种强大的免疫原，由于其重复的结构排列以及对特定B细胞受体的亲和力，能够引发强烈的保护性抗体反应。相比之下，由于抗原呈递细胞摄取和加工效率低下，VLPs引发的T细胞反应可能较弱。我们在此报告一种新策略，通过共价偶联M1（一种经工程改造的链球菌超抗原SMEZ2，它能高亲和力结合MHC II但缺乏T细胞促有丝分裂能力）来增强乙肝病毒核衣壳这种VLP的T细胞反应性。M1：乙肝核心抗原（HBcAg）偶联物与树突状细胞结合，并有效内吞至晚期内体。用M1：HBcAgs脉冲处理的人树突状细胞比用天然衣壳脉冲处理的细胞更有效地刺激了乙肝病毒特异性CD8(+) T细胞，这表明经修饰的VLP能更有效地被抗原呈递细胞交叉呈递。M1的偶联还能够显著诱导针对常见T辅助表位的人CD4(+) T细胞产生更强的反应性。这些研究表明重组超抗原作为灵活的分子佐剂的潜力，其可被纳入各种亚单位疫苗平台，从而增强人类的T细胞反应性。
