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

γδ T 细胞在胎儿和婴儿抵抗疟疾的免疫防御中的作用

• 批准号: 10299551
• 负责人: MARGARET E FEENEY
• 金额: $ 65.57万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-15 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10299551
• 关键词: Acute; Adult; Africa South of the Sahara; Antibodies; Antigen Presentation; Antigens; Antimalarials; Attenuated; Birth; Blood Circulation; Blood specimen; Cells; Cellular biology; Cessation of life; Characteristics; Child; Chronic; Data; Dendritic Cells; Development; Differentiated Gene; Effector Cell; Environment; Exhibits; Exposure to; Fetus; Fostering; Frequencies; Funding; Gene Expression; Genes; Grant; Granzyme; Growth; Heterogeneity; Human; Immune; Immune response; Immunity; Immunize; In Vitro; Individual; Infant; Infection; Inflammatory; Interferon Type II; Life; Lymphocyte; Lymphocyte Subset; Malaria; Malaria Vaccines; Mediating; Mononuclear; Mothers; Mus; Natural Immunity; Parasitemia; Parasites; Peripheral Blood Mononuclear Cell; Phagocytosis; Phenotype; Placenta; Plasmodium falciparum; Play; Population; Pregnancy; Preventive vaccine; Primary Infection; Proliferating; Recording of previous events; Role; Sampling; Source; Sporozoites; T cell response; T-Cell Development; T-Lymphocyte; T-cell receptor repertoire; TNF gene; Technology; Umbilical Cord Blood; Vaccines; Work; adaptive immune response; adaptive immunity; base; butyrophilin; cohort; cytokine; differential expression; early childhood; effector T cell; experimental study; extracellular; fetal; fetal blood; global health; granulysin; immunogenicity; immunoregulation; improved; in utero; in vivo; infancy; infant infection; malaria infection; neonate; novel; placental malaria; postnatal; prenatal; prenatal exposure; prospective; response; single cell sequencing; transcriptomics; uptake; volunteer; γδ T cells

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.

表达γδ TCR的T细胞是在人类妊娠期间首先发育的，并且具有许多特异性。 这些特点使它们特别适合于保护胎儿和婴儿。不同于常规 αβ T细胞、γδ T细胞识别非肽类抗原，并可表现出快速的、先天性的效应细胞 这些功能不依赖于先前的抗原暴露，也不依赖于树突细胞的引发， 在早期生命中功能不成熟。γδ T细胞亚群（Vγ9Vδ2）对磷酸化抗原应答 由恶性疟原虫通过一种独特的呈现方式产生， 亲丁酸蛋白分子。Vγ 9VS2 T细胞在体外抑制寄生虫复制并与 在体内保护免受恶性疟原虫寄生虫血症。值得注意的是，表达A β的Vγ 9VS2 T细胞， 磷酸化抗原反应性γδ TCR和预编程效应器功能已经存在于胎儿中， 妊娠中期出血。这些胎儿Vγ 9VS2 T细胞具有高的炎症潜能，并且可以被免疫抑制。 在刺激后迅速活化产生IFNγ和颗粒酶。此外，他们表示， 具有不同序列特征的半不变TCR，包括有限的连接多样性 以及差异基因片段的使用，这将它们与后来产生的Vγ9Vδ2 T细胞区分开来。 生活考虑到Vγ 9VS2 T细胞对恶性疟原虫的固有反应性，我们假设这些T细胞对恶性疟原虫的反应性是特异性的。 在婴儿急性疟疾感染期间， 和年幼的儿童，在适应性免疫反应发展之前。我们将使用纵向 先前从乌干达大量婴儿中收集的样本，包括脐带血 单核细胞和婴儿PBMC，以确定Vγ9Vδ2 T细胞如何响应疟疾抗原 在子宫内和幼儿期接触。在第一个目标中，我们将描述膨胀， 婴儿中γδ T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Vγ9Vδ2 T细胞反应是否不同， 根据初次接触疟疾的时间。在第二个目标中，我们将评估 子宫内和生命早期疟疾抗原暴露对γδ TCR序列库的影响。这一目标 将整合单细胞测序技术，将转录组信息与TCR配对， 单个细胞的序列数据，使我们能够解决许多潜在的表型来源， 以及在批量细胞分析水平上观察到的功能异质性。最后，Vγ9Vδ2 T细胞具有 已经显示出类似APC的能力，包括吞噬作用，抗原呈递，甚至 初始T细胞的引发。这些功能在婴儿期可能特别相关， 专职APC是不成熟的并且呈递抗原能力差。因此，在第三个目标中， 研究Vγ9Vδ2 T细胞是否在胎儿和新生儿中发挥额外的作用， 直接效应子功能，包括摄取和呈递抗原至常规αβ T 细胞和FcR介导的调理抗原的识别。 总之，这些实验将阐明一个独特的半先天的功能能力， 效应T细胞群体及其在生命早期抗疟疾保护中的作用。