T Cell Regulatory and Suppression Mechanisms in Malaria

我们在2022财年发表的工作包括： Zaidi I，Duffy PE. PfSPZ疫苗吸取了教训。2021. Cell Press.十二月十日。 在肯尼亚，第一次在婴儿中进行的减毒全生物PfSPZ疫苗试验显示，对疟疾感染几乎没有效果，而在非洲成年人中进行的试验一再观察到保护作用。免疫反应的差异为可能的原因提供了线索。在这篇评论中，我们探讨了可能阻碍PfSPZ疫苗诱导保护性免疫的因素，包括疟疾的影响和疟疾流行地区免疫前假定抗疟治疗的影响。 我们在本报告所述期间未公布的进展包括以下进展： 我们利用人体试验和疟疾模型的样本，扩展了完整子孢子疟疾疫苗的免疫细胞研究。Sanaria PfSPZ疫苗由放射减毒的恶性疟原虫（Pf）子孢子（SPZ）组成，保护免受Pf感染，并且V δ 2+ gd T细胞（下文称为Vd2细胞）扩增与诱导无菌免疫相关。在临床前模型中，赋予无菌免疫的保护性CD8+ T细胞的扩增在SPZ疫苗接种期间需要gd T细胞，但在感染性攻击期间不需要gd T细胞作为效应子。 为了更深入地了解有助于PfSPZ疫苗保护的免疫细胞亚群，我们对来自一项美国PfSPZ疫苗试验和两项马里PfSPZ疫苗试验的48名受试者进行了全血RNA测序，并应用新工具报告基因表达水平和估算免疫细胞变化。我们整理了144个已发表的RNAseq数据集，涵盖27个分类的人类免疫细胞亚群，包括先天性，B和T细胞亚群和分化状态，然后进行了27向差异表达分析，并将每个基因与其最高差异表达的细胞类型相关联，以创建典型的细胞类型转录组。我们关联转录组，以数学方式将每个PfSPZ参与者样本描述为27细胞型复合混合物，并量化细胞类型比例的变化。 通过这种方法，我们鉴定了在PfSPZ疫苗接种期间扩增并与无菌免疫相关的Vd2细胞亚群。同时，使用完整SPZ疫苗接种的小鼠模型，我们鉴定了在SPZ免疫的小鼠中发挥这种作用并且需要产生保护性CD8 T细胞的相应gd T细胞亚群。

Our published work in FY22 included: Zaidi I, Duffy PE. PfSPZ Vaccine learns a lesson. 2021. Med, Cell Press. Dec 10. In Kenya, the first trial of the attenuated whole organism PfSPZ Vaccine in infants has shown little efficacy against malaria infection, whereas trials in African adults have repeatedly observed protection. Differences in immune responses offer clues to the possible reasons. In this commentary, we explored the factors that might hinder the induction of protective immunity by PfSPZ Vaccine, including the effects of malaria and of presumptive antimalarial treatment before immunization in malaria-endemic areas. Our unpublished progress during this reporting period includes the following advances: We extended our immune cell studies of whole sporozoite malaria vaccines, using samples from human trials and models of malaria. Sanaria PfSPZ Vaccine, comprised of radiation-attenuated Plasmodium falciparum (Pf) sporozoites (SPZ), protects against Pf infection, and V delta 2+ gd T cell (hereafter Vd2 cell) expansion has been associated with induction of sterile immunity. In preclinical models, expansion of protective CD8+ T cells that confer sterile immunity require gd T cells during SPZ vaccinations, but gd T cells are not required as effectors during infectious challenge. To gain a deeper insight into immune cell subsets contributing to PfSPZ Vaccine protection, we performed whole blood RNA sequencing on 48 subjects from one US and two Mali PfSPZ Vaccine trials and applied novel tools to report gene expression level and impute immune cell changes. We collated 144 published RNAseq datasets spanning 27 sorted human immune cell subsets, including innate, B, and T cell subpopulations and differentiation status, then performed 27-way differential expression analysis and associated each gene to its cell type of highest differential expression to create canonical cell-type transcriptomes. We associated transcriptomes to mathematically describe each PfSPZ participant sample as a 27-cell-type composite mix and quantify changes in cell-type proportions. By this approach, we identified a subset of Vd2 cells that expand during PfSPZ vaccinations and associate with sterile immunity. In parallel, using a mouse model of whole SPZ vaccination, we identified the corresponding subset of gd T cells that play this role in SPZ-immunized mice and that are required to generate protective CD8 T cells.