Immunomodulation of vaccine-induced CD8+ T cell responses through early life exposure to chronic maternal schistosomiasis

全球有2.21亿人感染血吸虫病，血吸虫病是低收入和中等收入国家最常见的传染病之一，与疟疾并驾齐驱，通过水接触传播病原体严重阻碍了以前抗击这种疾病的措施。估计有4000万妇女在怀孕期间感染，产妇感染--除了低出生体重和贫血--与后代过敏性表型(例如湿疹)的变化有关。事实上，我们已经能够在小鼠模型中表明，受感染的雌性小鼠的后代受到保护，免受过敏性呼吸道炎症(AAI)的影响，并将这种改变的免疫表型保留到成年。然而，最近的初步工作表明，这些后代的变化超出了修改后的AAI，并不局限于CD4T细胞反应。不同的疫苗接种模式显示CD8 T细胞的反应性有显著差异：基于病毒载体(MVA)的现代疫苗在这些后代中可能比传统佐剂疫苗具有决定性优势。前者在有效和保护性免疫方面发挥着越来越重要的作用，不仅是针对病毒，也是针对原生动物，例如疟疾病原体，鉴于各国与蠕虫疾病的共生性，原虫可能是核心。由于这种修改后的免疫表型持续到成年，我们怀疑子宫内的“免疫训练”受感染相关的母体炎症状态的影响。主要因素可能是修饰的调控网络的诱导，这最终抑制了抗原提呈细胞通过经典疫苗有效地激活CD8 T细胞的能力，但现代载体疫苗可以克服这一点。为了进一步阐明这一过程中涉及的机制，我们将使用不同的疫苗模型来区分抗原提呈细胞的表型和功能的变化，作为CD8T细胞启动诱导和调节的中心开关点，并与CD8T细胞内在的发育和反应性变化进行比较，例如通过转录组、亚群频率和刺激分析。这些调查的结果将有助于了解母体炎症状态与儿童免疫系统发育之间的相互作用，并最终有助于在蠕虫流行地区制定适应的疫苗接种战略。

With 221 million infected people worldwide, schistosomiasis is one of the most common infectious diseases in LMIC (low and middle income countries) alongside malaria, and the transmission of the pathogen by water contact has significantly hampered previous measures to combat the disease. An estimated 40 million women are infected during pregnancy and maternal infection - in addition to low birth weight and anemia - has been associated with changes in allergic phenotypes (e.g. eczema) of offspring. In fact, we have been able to show in the mouse model that offspring of infected female mice are protected from allergic airway inflammation (AAI) and retain this altered immunophenotype into adulthood. However, recent preliminary work shows that the changes in these offspring go beyond modified AAI and are not limited to CD4+ T cell responses. Different vaccination models showed marked differences in the reactivity of CD8+ T-cells: modern vaccines based on viral vectors (MVA) may have a decisive advantage over classically adjuvanted vaccines in these offspring. The former play an increasingly important role for an effective and protective immunity against viruses but also against protozoa such as plasmodia, the malaria pathogen, which may be central in view of the coendemicity with helminth diseases in the respective countries. Because this modified immunological phenotype persists into adulthood, we suspect that "immunological training" in utero is influenced by infection-related maternal inflammatory status. The main factors may be the induction of modified regulatory networks, which ultimately inhibit the ability of antigen-presenting cells to effectively prime CD8+ T-cells by classical, for example alum-based vaccines in offspring, but which can be overcome by modern vector-based vaccines. In order to further clarify the mechanisms involved in this process, we will use different vaccine models to differentiate changes in phenotype and functionality of antigen-presenting cells as a central switch point in the induction and regulation of CD8+ T-cell priming as compared to CD8+ T cell intrinsic developmental and reactivity changes e.g. by transcriptome, subpopulation frequency and stimulation analysis. The results of these investigations will make an important contribution to the understanding of the interplay between maternal inflammatory status and the development of the child's immune system and ultimately to the development of adapted vaccination strategies in helminth-endemic areas.