经辐射减毒的疟原虫孢子免疫后,抗疟肝脏期免疫需要极端的 CD8 T 细胞。

Extreme CD8 T cell requirements for anti-malarial liver-stage immunity following immunization with radiation attenuated sporozoites.

机构信息

Department of Microbiology, University of Iowa, Iowa City, Iowa, United States of America.

出版信息

PLoS Pathog. 2010 Jul 15;6(7):e1000998. doi: 10.1371/journal.ppat.1000998.

Abstract

Radiation-attenuated Plasmodium sporozoites (RAS) are the only vaccine shown to induce sterilizing protection against malaria in both humans and rodents. Importantly, these "whole-parasite" vaccines are currently under evaluation in human clinical trials. Studies with inbred mice reveal that RAS-induced CD8 T cells targeting liver-stage parasites are critical for protection. However, the paucity of defined T cell epitopes for these parasites has precluded precise understanding of the specific characteristics of RAS-induced protective CD8 T cell responses. Thus, it is not known whether quantitative or qualitative differences in RAS-induced CD8 T cell responses underlie the relative resistance or susceptibility of immune inbred mice to sporozoite challenge. Moreover, whether extraordinarily large CD8 T cell responses are generated and required for protection following RAS immunization, as has been described for CD8 T cell responses following single-antigen subunit vaccination, remains unknown. Here, we used surrogate T cell activation markers to identify and track whole-parasite, RAS-vaccine-induced effector and memory CD8 T cell responses. Our data show that the differential susceptibility of RAS-immune inbred mouse strains to Plasmodium berghei or P. yoelii sporozoite challenge does not result from host- or parasite-specific decreases in the CD8 T cell response. Moreover, the surrogate activation marker approach allowed us for the first time to evaluate CD8 T cell responses and protective immunity following RAS-immunization in outbred hosts. Importantly, we show that compared to a protective subunit vaccine that elicits a CD8 T cell response to a single epitope, diversifying the targeted antigens through whole-parasite RAS immunization only minimally, if at all, reduced the numerical requirements for memory CD8 T cell-mediated protection. Thus, our studies reveal that extremely high frequencies of RAS-induced memory CD8 T cells are required, but may not suffice, for sterilizing anti-Plasmodial immunity. These data provide new insights into protective CD8 T cell responses elicited by RAS-immunization in genetically diverse hosts, information with relevance to developing attenuated whole-parasite vaccines.

摘要

辐射减毒疟原虫孢子(RAS)是唯一被证明可在人类和啮齿动物中诱导抗疟疾绝育保护的疫苗。重要的是,这些“全寄生虫”疫苗目前正在进行人类临床试验评估。对近交系小鼠的研究表明,针对肝期寄生虫的 RAS 诱导的 CD8 T 细胞对于保护至关重要。然而,由于这些寄生虫缺乏明确的 T 细胞表位,因此无法精确了解 RAS 诱导的保护性 CD8 T 细胞反应的具体特征。因此,尚不清楚 RAS 诱导的 CD8 T 细胞反应的数量或质量差异是否是免疫近交系小鼠对孢子挑战的相对抗性或敏感性的基础。此外,在 RAS 免疫接种后是否会产生异常大量的 CD8 T 细胞反应并需要这些反应来进行保护,就像已经描述的针对单一抗原亚单位疫苗接种的 CD8 T 细胞反应一样,目前尚不清楚。在这里,我们使用替代 T 细胞激活标志物来鉴定和跟踪全寄生虫、RAS 疫苗诱导的效应和记忆 CD8 T 细胞反应。我们的数据表明,RAS 免疫近交系小鼠对伯氏疟原虫或约氏疟原虫孢子挑战的不同敏感性并非源自宿主或寄生虫特异性的 CD8 T 细胞反应下降。此外,替代激活标志物方法使我们首次能够在近交系宿主中评估 RAS 免疫接种后的 CD8 T 细胞反应和保护性免疫。重要的是,我们表明,与仅引发单个表位的 CD8 T 细胞反应的保护性亚单位疫苗相比,通过全寄生虫 RAS 免疫接种使靶向抗原多样化,即使有影响,也只是最小程度地降低了记忆 CD8 T 细胞介导的保护所需的数量要求。因此,我们的研究表明,需要极高频率的 RAS 诱导的记忆 CD8 T 细胞来实现抗疟原虫的绝育免疫,但可能还不够。这些数据为在遗传上多样化的宿主中 RAS 免疫引发的保护性 CD8 T 细胞反应提供了新的见解,这些信息对于开发减毒全寄生虫疫苗具有重要意义。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/73dc/2904779/ade6fc8e6def/ppat.1000998.g001.jpg

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