Decidual NK response to infection

蜕膜 NK 对感染的反应

• 批准号: 10623205
• 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/10623205
• 关键词: Awareness; Bacteria; Cell Death; Cell secretion; Cells; Conflict (Psychology); Cytomegalovirus; Cytoplasm; Cytoplasmic Granules; Cytoprotection; 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; 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; Predisposition; 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; Vascular remodeling; Villous; 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; maternal immune system; 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.

蜕膜 NK 细胞 (dNK) 是母体-胎儿界面上最大的母体免疫细胞群 妊娠早期，直接接触胎儿绒毛外滋养细胞（EVT），侵入蜕膜 重塑脉管系统以建立胎盘的血液供应。 dNK 和 EVT 之间的直接联系 挑战母体免疫系统，该系统必须耐受胎儿细胞，但仍能防止感染。如何 dNK 保护胎盘和胎儿免受感染的作用尚不清楚。最有临床意义的感染 胎盘和胎儿是由细胞内病原体（细菌、寄生虫和病毒）引起的，其杀手 淋巴细胞（NK 和细胞毒性 T 淋巴细胞）是全身保护性免疫的关键。在前三个月， 当感染对胎儿造成最严重的后果时，蜕膜中的 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 NK 细胞靶标，其溶细胞作用 与外周血 NK 细胞相比，活性降低。此外，虽然 dNK 与 EVT 建立了联系，但他们 不脱粒或杀死 人类巨细胞病毒感染的 EVT。这些发现强调了 母体免疫细胞清除胎盘感染并防止病原体传播给未出生的孩子。 该提案研究了我们最近发现的一种新颖且令人兴奋的机制，通过该机制 dNK 可以杀死 L. 滋养细胞内的单核细胞增生李斯特菌 (Lm)，而不杀死宿主细胞。 dNK 表达大量颗粒溶素 (GNLY)，一种在细胞毒性颗粒和细胞质中发现的抗菌肽，优先破坏 微生物，相对于哺乳动物，膜。我们的初步数据表明 dNK 建立了纳米管 细胞质与 EVT 的连接。不形成传统的免疫突触或脱颗粒，dNK 通过纳米管将 GNLY 转移至 EVT，但不转移其他细胞毒性分子（穿孔素、颗粒酶），否则会杀死 宿主细胞。这种机制为妊娠期的免疫困境提供了一个优雅的解决方案——防御 抵抗感染，同时保持胎儿和胎盘的耐受性。据我们所知，这是第一个 纳米管免疫功能的证据。 GNLY 和其他潜在生物活性的纳米管转移 从 dNK 到 EVT 的分子有助于控制细胞内感染并调节滋养层功能。我们的 目标是确认我们的初步数据，即细胞内微生物，而不是胎儿细胞，被杀死 GNLY 的 dNK 转移，独立于穿孔素和颗粒酶；确定哪些受感染的母体和胎儿细胞 胎盘中 dNK 的保护作用是什么？探索纳米管的机制 形成、哪些分子被转移以及哪些妊娠中重要的病原体容易受到影响。这 GNLY 和 dNK 的保护作用也将在人类胎盘组织外植体和小鼠中进行评估 比较 GNLY 转基因 (Tg) 和 WT 小鼠感染后的妊娠结局， 表达GNLY。这些外植体和体内研究将调查三种妊娠病原体 - Lm，B 组 链球菌 (GBS) 和弓形虫。

项目成果

The NK cell receptor NKp46 recognizes ecto-calreticulin on ER-stressed cells.

• DOI: 10.1038/s41586-023-05912-0
• 发表时间: 2023-04
• 期刊: NATURE
• 影响因子: 64.8
• 作者: Sen Santara, Sumit;Lee, Dian-Jang;Crespo, Angela;Hu, Jun Jacob;Walker, Caitlin;Ma, Xiyu;Zhang, Ying;Chowdhury, Sourav;Meza-Sosa, Karla F.;Lewandrowski, Mercedes;Zhang, Haiwei;Rowe, Marjorie;McClelland, Arthur;Wu, Hao;Junqueira, Caroline;Lieberman, Judy
• 通讯作者: Lieberman, Judy