Decidual NK response to infection

蜕膜 NK 对感染的反应

• 批准号: 10160812
• 负责人: Judy Lieberman
• 金额: $ 83.58万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-19 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10160812
• 关键词: Allogenic; Awareness; Bacteria; Blood Vessels; Cell Death; Cells; Conflict (Psychology); Cytomegalovirus; Cytoplasmic Granules; Cytosol; Cytotoxic T-Lymphocytes; Data; Decidua; Decidual Cell; Fetal Distress; Fetal Growth Retardation; Fetal Tissues; Fetus; First Pregnancy Trimester; Goals; Granzyme; Human; Immune; Immune system; Immunity; Infection; Invaded; Lead; Ligands; Listeria monocytogenes; Lymphocyte; Lymphocyte Subset; Maternal-Fetal Exchange; Mediating; Membrane; Microbe; Mus; Nanotubes; Natural Immunity; Natural Killer Cells; Parasites; Pathway interactions; Placenta; Placentation; Population; Pre-Eclampsia; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Premature Birth; Premature Labor; Process; Role; Side; Spontaneous abortion; Streptococcus Group B; T-Lymphocyte; Testing; Tissues; Toxoplasma gondii; Transgenic Mice; Transgenic Organisms; Vascular blood supply; Virus; adaptive immunity; antimicrobial peptide; cell killing; cell type; clinically significant; congenital anomaly; cytokine; cytotoxic; extracellular; fetal; fetal immunity; fetal loss; fetus cell; fungus; granulysin; immune function; immunological synapse; in vivo; insight; intrauterine infection; microbial; migration; novel; pathogen; perforin; peripheral blood; placental infection; prevent; receptor; response; transmission process; trophoblast; unborn child

Decidual NK cells (dNK), the largest population of maternal immune cells at the maternal-fetal interface in the first trimester of pregnancy, directly contact fetal extravillous trophoblasts (EVT), which invade the decidua to remodel the vasculature to establish the blood supply to the placenta. The direct contact between dNK and EVT challenges the maternal immune system, which must tolerate fetal cells, but still protect against infection. How dNK protect the placenta and fetus from infection is not well understood. Most clinically significant infections of the placenta and fetus are caused by intracellular pathogens (bacteria, parasites and viruses), for which killer lymphocytes (NK and cytotoxic T lymphocytes) are key to systemic protective immunity. In the first trimester, when infection has the most serious fetal consequences, there are few T cells in the decidua. Although dNK have cytotoxic granules, express all the cytotoxic molecules, and kill conventional NK cell targets, their cytolytic activity is reduced compared to peripheral blood NK cells. Moreover, although dNK form contacts with EVT, they do not degranulate or kill human cytomegalovirus-infected EVT. These findings emphasize the difficulties of maternal immune cells to clear placental infections and prevent transmission of pathogens to the unborn child. This proposal investigates a novel and exciting mechanism we recently discovered by which dNK kill L. monocytogenes (Lm) inside trophoblasts, without killing the host cell. dNK express large amounts of granulysin (GNLY), an antimicrobial peptide found both in cytotoxic granules and the cytosol that preferentially disrupts microbial, relative to mammalian, membranes. Our preliminary data suggest that dNK establish nanotube cytoplasmic connections to EVT. Without forming a conventional immune synapse or degranulating, dNK transfer GNLY via nanotubes to EVT, but not other cytotoxic molecules (perforin, granzymes), which would kill the host cell. This mechanism provides an elegant solution to the immune dilemma of pregnancy – defense against infection while maintaining tolerance of the fetus and placenta. As far as we are aware, this is the first evidence for an immune function of nanotubes. Nanotube transfer of GNLY and potentially other bioactive molecules from dNK to EVT helps control intracellular infection and could regulate trophoblast functions. Our goals are to confirm our preliminary data showing that intracellular microbes, but not fetal cells, are killed by dNK transfer of GNLY, independently of perforin and granzymes; identify which infected maternal and fetal cells in the placenta dNK protect and by what mechanism; explore the mechanism responsible for nanotube formation, which molecules are transferred and which pathogens important in pregnancy are susceptible. The protective role of GNLY and dNK will also be evaluated in human placental tissue explants and in mice by comparing pregnancy outcomes following infection of GNLY-transgenic (Tg) and WT mice, which do not express GNLY. These explant and in vivo studies will investigate three pathogens of pregnancy - Lm, Group B Streptococci (GBS) and Toxoplasma gondii.

deciDual NK细胞（DNK），这是母亲界面的母体免疫细胞中最大的母体免疫细胞群体 怀孕的头三个月，直接接触胎儿跨性滋养细胞（EVT），该滋养细胞入侵了决定 重塑脉管系统，以建立给子宫的血液供应。 DNK和EVT之间的直接接触 挑战母体免疫系统，必须耐受胎儿细胞，但仍然可以防止感染。如何 DNK保护斑点和胎儿免于感染尚不清楚。大多数临床意义的感染 斑点和胎儿是由细胞内病原体（细菌，寄生虫和病毒）引起的，为此杀手 淋巴细胞（NK和细胞毒性T淋巴细胞）是全身性保护免疫的关键。在头三个月， 当感染具有最严重的胎儿后果时，决策中的T细胞很少。虽然DNK 具有细胞毒性颗粒，表达所有细胞毒性分子并杀死常规的NK细胞靶标 与外周血NK细胞相比，活性降低。而且，尽管DNK与EVT形成了联系，但 不要脱粒或杀死 人类巨细胞病毒感染的EVT。这些发现强调了 母体免疫细胞清除斑点感染并防止病原体向未出生的儿童传播。 该提案调查了我们最近发现的一种新颖而令人兴奋的机制，DNK Kill L. 单核细胞增生剂（LM）在滋养细胞内，而无需杀死宿主细胞。 DNK表达大量颗粒素 （gnly），一种在细胞毒性颗粒中发现的抗菌胡椒和优先破坏的细胞质 微生物，相对于哺乳动物，膜。我们的初步数据表明DNK建立纳米管 细胞质连接到EVT。不形成常规免疫突触或脱粒，DNK 通过纳米管转移至EVT，而不是其他细胞毒性分子（穿孔蛋白，颗粒酶），它将杀死 宿主单元。这种机制为怀孕的免疫困境提供了优雅的解决方案 - 防御 在维持胎儿和plapeta的耐受性的同时反对感染。据我们所知，这是第一个 纳米管的免疫学功能的证据。纳米管转移GNLY和潜在的其他生物活性 从DNK到EVT的分子有助于控制细胞内感染，并可能调节滋养细胞功能。我们的 目标是确认我们的初步数据，表明细胞内微生物而不是胎儿细胞被杀死 Gnly的DNK转移，独立于穿孔和颗粒酶；确定哪些感染的Matal和胎儿细胞 在plapeta dnk保护和通过什么机制；探索负责纳米管的机制 形成，分子被转移，哪些病原体在妊娠中很重要。 GNLY和DNK的保护作用也将在人类斑点组织外植体中评估，并在小鼠中通过 比较感染Gnly-转基因（TG）和WT小鼠后的妊娠结局 表达gnly。这些外植体和体内研究将研究三种怀孕的病原体-LM，B组 链球菌（GBS）和弓形虫Gondii。