Department of Cellular Immunology, Malaria Vaccine Branch, Walter Reed Army Institute of Research, Silver Spring, MD, United States.
Laboratory of Malaria Immunology and Vaccinology, National Institute of Allergy and Infectious Diseases, (NIH), Rockville, MD, United States.
Front Immunol. 2018 Jan 29;9:91. doi: 10.3389/fimmu.2018.00091. eCollection 2018.
We recently identified novel (Pb) liver stage (LS) genes that as DNA vaccines significantly reduce Pb LS parasite burden (LPB) in C57Bl/6 (B6) mice through a mechanism mediated, in part, by CD8 T cells. In this study, we sought to determine fine antigen (Ag) specificities of CD8 T cells that target LS malaria parasites. Guided by algorithms for predicting MHC class I-restricted epitopes, we ranked sequences of 32 Pb LS Ags and selected ~400 peptides restricted by mouse H-2K and H-2D alleles for analysis in the high-throughput method of caged MHC class I-tetramer technology. We identified a 9-mer H-2K restricted CD8 T cell epitope, Kb-17, which specifically recognized and activated CD8 T cell responses in B6 mice immunized with Pb radiation-attenuated sporozoites (RAS) and challenged with infectious sporozoites (spz). The Kb-17 peptide is derived from the recently described novel protective Pb LS Ag, PBANKA_1031000 (MIF4G-like protein). Notably, immunization with the Kb-17 epitope delivered in the form of a minigene in the adenovirus serotype 5 vector reduced LPB in mice infected with spz. On the basis of our results, Kb-17 peptide was available for CD8 T cell activation and recall following immunization with Pb RAS and challenge with infectious spz. The identification of a novel MHC class I-restricted epitope from the protective Pb LS Ag, MIF4G-like protein, is crucial for advancing our understanding of immune responses to Plasmodium and by extension, toward vaccine development against malaria.
我们最近发现了新型 （Pb） 肝期（LS）基因，这些基因作为 DNA 疫苗，通过部分由 CD8 T 细胞介导的机制，显著降低 C57Bl/6（B6）小鼠中的 Pb LS 寄生虫负担（LPB）。在这项研究中，我们试图确定针对 LS 疟原虫的 CD8 T 细胞的精细抗原（Ag）特异性。在预测 MHC 类 I 限制性表位的算法的指导下，我们对 32 种 Pb LS 抗原的序列进行了排序，并选择了约 400 种受小鼠 H-2K 和 H-2D 等位基因限制的肽进行分析，使用 Cage MHC 类 I-tetramer 技术的高通量方法。我们鉴定了一个 9 -mer H-2K 限制性 CD8 T 细胞表位 Kb-17，该表位特异性识别和激活 B6 小鼠对 Pb 辐射减毒孢子（RAS）免疫和感染性孢子（spz）挑战的 CD8 T 细胞反应。Kb-17 肽来源于最近描述的新型保护性 Pb LS Ag，PBANKA_1031000（MIF4G 样蛋白）。值得注意的是，用腺病毒血清型 5 载体中的 minigene 形式递送 Kb-17 表位的免疫可降低感染 spz 的小鼠的 LPB。基于我们的结果，在用 Pb RAS 免疫和用感染性 spz 挑战后，Kb-17 肽可用于 CD8 T 细胞的激活和回忆。从保护性 Pb LS Ag，MIF4G 样蛋白中鉴定出一种新型 MHC 类 I 限制性表位，对于深入了解对疟原虫的免疫反应以及疟疾疫苗的开发至关重要。
