Doll Katherine L, Pewe Lecia L, Kurup Samarchith P, Harty John T
Department of Microbiology, University of Iowa, Iowa City, IA 52242;
Department of Microbiology, University of Iowa, Iowa City, IA 52242; Department of Pathology, University of Iowa, Iowa City, IA 52242; and Interdisciplinary Program in Immunology, University of Iowa, Iowa City, IA 52242
J Immunol. 2016 May 15;196(10):4253-62. doi: 10.4049/jimmunol.1600155. Epub 2016 Apr 15.
Despite decades of research, malaria remains a global health crisis. Current subunit vaccine approaches do not provide efficient long-term, sterilizing immunity against Plasmodium infections in humans. Conversely, whole parasite vaccinations with their larger array of target Ags have conferred long-lasting sterilizing protection to humans. Similar studies in rodent models of malaria reveal that CD8(+) T cells play a critical role in liver-stage immunity after whole parasite vaccination. However, it is unknown whether all CD8(+) T cell specificities elicited by whole parasite vaccination contribute to protection, an issue of great relevance for enhanced subunit vaccination. In this article, we show that robust CD8(+) T cell responses of similar phenotype are mounted after prime-boost immunization against Plasmodium berghei glideosome-associated protein 5041-48-, sporozoite-specific protein 20318-325-, thrombospondin-related adhesion protein (TRAP) 130-138-, or circumsporozoite protein (CSP) 252-260-derived epitopes in mice, but only CSP252-260- and TRAP130-138-specific CD8(+) T cells provide sterilizing immunity and reduce liver parasite burden after sporozoite challenge. Further, CD8(+) T cells specific to sporozoite surface-expressed CSP and TRAP proteins, but not intracellular glideosome-associated protein 50 and sporozoite-specific protein 20, efficiently recognize sporozoite-infected hepatocytes in vitro. These results suggest that: 1) protection-relevant antigenic targets, regardless of their immunogenic potential, must be efficiently presented by infected hepatocytes for CD8(+) T cells to eliminate liver-stage Plasmodium infection; and 2) proteins expressed on the surface of sporozoites may be good target Ags for protective CD8(+) T cells.
尽管经过了数十年的研究，疟疾仍然是全球健康危机。目前的亚单位疫苗方法不能提供针对人类疟原虫感染的高效长期、绝育免疫。相反，含有更多种类靶抗原的全寄生虫疫苗接种已为人类提供了持久的绝育保护。在疟疾啮齿动物模型中进行的类似研究表明，CD8(+) T细胞在全寄生虫疫苗接种后的肝期免疫中起关键作用。然而，尚不清楚全寄生虫疫苗接种引发的所有CD8(+) T细胞特异性是否都有助于提供保护，这一问题对于增强亚单位疫苗接种具有重要意义。在本文中，我们表明，在针对伯氏疟原虫滑行体相关蛋白50 41-48、子孢子特异性蛋白20 318-325、血小板反应蛋白相关粘附蛋白(TRAP) 130-138或环子孢子蛋白(CSP) 252-260衍生表位的初免-加强免疫后，小鼠会产生类似表型的强大CD8(+) T细胞反应，但只有CSP252-260和TRAP130-138特异性CD8(+) T细胞在子孢子攻击后提供绝育免疫并减轻肝脏寄生虫负担。此外，子孢子表面表达的CSP和TRAP蛋白特异性的CD8(+) T细胞，而不是细胞内滑行体相关蛋白50和子孢子特异性蛋白20特异性的CD8(+) T细胞，在体外能有效识别子孢子感染的肝细胞。这些结果表明：1) 与保护相关的抗原靶点，无论其免疫原性潜力如何，必须由受感染的肝细胞有效呈递，以便CD8(+) T细胞消除肝期疟原虫感染；2) 子孢子表面表达的蛋白质可能是保护性CD8(+) T细胞的良好靶抗原。
