The role of γδ T cells in fetal and infant immune defense against malaria

表达γδTcR的T细胞是人类妊娠期间最早发育的T细胞，具有许多 使其独一无二地适合保护胎儿和婴儿的特点。与传统不同 αβT细胞，γδT细胞识别非肽抗原，并能表现出快速的，先天的效应 功能不依赖于先前的抗原暴露，也不依赖于树突状细胞的启动，这 在早期生活中在功能上不成熟。γδT细胞亚群(Vγ9Vδ2)对磷抗原的反应 由恶性疟原虫通过一种独特的呈现方式产生，其无处不在的表达方式 丁咯菲林分子。V-γ9V-δ-2 T细胞体外抑制寄生虫复制 具有体内对恶性疟原虫寄生虫病的保护作用。值得注意的是，表达a基因的Vγ9Vδ2T细胞 磷酸抗原反应性γδ受体和预编程效应功能在胎儿中已经存在 妊娠中期的血液。这些胎儿Vγ9Vδ2 T细胞具有高炎症潜能，可以 在刺激下迅速激活以产生干扰素γ和颗粒酶。此外，他们还表示 具有不同序列特征的半不变TCR，包括有限的连接多样性 和差异基因片段的使用，将它们与后来生成的Vγ9Vδ2 T细胞区分开来 生活。鉴于Vγ9Vδ2T细胞对恶性疟原虫的固有反应性，我们假设这些 在婴儿急性疟疾感染中，细胞可能作为现成效应器发挥有益作用 和年幼的儿童，在适应性免疫反应形成之前。我们将使用纵向 之前从一大批乌干达婴儿身上收集的样本，包括脐带血 单个核细胞和婴儿PBMC，以确定Vγ9Vδ2T细胞对疟疾抗原的反应 在宫内和儿童早期暴露。在第一个目标中，我们将描述扩张的特征， 婴幼儿γδT细胞的分化、效应功能和增殖能力 产前和产后疟疾，使我们能够评估Vγ9Vδ2T细胞反应是否不同 根据最初接触疟疾的时间。在第二个目标中，我们将评估 在γδTCR序列库中，疟疾抗原在宫内和生命早期的暴露。这一目标 将结合单细胞测序技术，将转录信息与TCR配对 来自单个细胞的序列数据，使我们能够解析许多潜在的表型来源 以及在整体细胞分析水平上观察到的功能异质性。最后，Vγ9Vδ2 T细胞 已显示出类似于APC的能力，包括吞噬、抗原递呈，甚至 幼稚T细胞的启动。在婴儿期，这种功能可能特别重要，当 专业的APC不成熟，抗原提呈能力差。因此，在第三个目标中，我们将 研究Vγ9Vδ2T细胞是否在胎儿和新生儿中发挥额外的作用 即刻效应功能，包括对传统αβT细胞抗原的摄取和提呈 细胞和FCR介导的调理抗原识别。 总之，这些实验将阐明一种独特的半天生生物的功能能力 效应器T细胞群体及其在早期预防疟疾中的作用。

T cells expressing the γδ TCR are the first to develop during human gestation and possess many features that make them uniquely suited to protection of the fetus and infant. Unlike conventional αβ T cells, γδ T cells recognize non-peptide antigens and can exhibit rapid, innate-like effector functions that are not dependent on prior antigen exposure nor on priming by dendritic cells, which are functionally immature in early life. A subset of γδ T cells (Vγ9Vδ2) respond to phosphoantigens produced by Plasmodium falciparum via a unique mode of presentation by ubiquitously expressed butyrophilin molecules. Vγ9Vδ2 T cells inhibit parasite replication in vitro and are associated with protection from P. falciparum parasitemia in vivo. Remarkably, Vγ9Vδ2 T cells that express a phosphoantigen-reactive γδ TCR and pre-programmed effector functions are already present in fetal blood at mid-gestation. These fetal Vγ9Vδ2 T cells have high inflammatory potential and can be rapidly activated to produce IFNγ and granzymes upon stimulation. In addition, they express semi-invariant TCRs with distinct sequence characteristics, including limited junctional diversity and differential gene segment usage, that distinguish them from Vγ9Vδ2 T cells generated later in life. Given the intrinsic reactivity of Vγ9Vδ2 T cells to P. falciparum, we hypothesize that these cells may play a beneficial role as ready-made effectors during acute malaria infection of infants and young children, before an adaptive immune response has developed. We will use longitudinal samples previously collected from a large cohort of Ugandan infants, including cord blood mononuclear cells and infant PBMCs, to determine how Vγ9Vδ2 T cells respond to malaria antigen exposure in utero and during early childhood. In the first aim, we will characterize the expansion, differentiation, effector functions, and proliferative capacity of γδ T cells in infants following prenatal and postnatal malaria, enabling us to assess whether the Vγ9Vδ2 T cell response differs based on the timing of initial malaria exposure. In the second aim, we will evaluate the impact of malaria antigen exposure in utero and during early life on the γδ TCR sequence repertoire. This aim will incorporate single-cell sequencing technologies that pair transcriptomic information with TCR sequence data from individual cells, enabling us to resolve many potential sources of phenotypic and functional heterogeneity observed at the bulk cell analysis level. Lastly, Vγ9Vδ2 T cells have been shown to display APC-like capabilities including phagocytosis, antigen presentation, and even priming of naive T cells. Such functions may be of particular relevance during infancy, when professional APCs are immature and present antigen poorly. Therefore, in the third aim, we will investigate whether Vγ9Vδ2 T cells play additional roles in the fetus and neonate, beyond their immediate effector functions, including uptake and presentation of antigens to conventional αβ T cells and FcR-mediated recognition of opsonized antigens. Together, these experiments will illuminate the functional capabilities of a unique semi-innate effector T cell population and its role in protection against malaria during early life.