Decidual NK response to infection

蜕膜 NK 对感染的反应

基本信息

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
项目类别：
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

项目摘要

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 之间的直接接触。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。 dNK 保护胎盘和胎儿免受感染的作用尚不清楚。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）是妊娠早期的全身保护性免疫的关键。当感染对胎儿造成最严重的后果时，蜕膜中的 T 细胞很少。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，dNK 活性降低。此外，尽管 dNK 与 EVT 形成接触，但它们的活性较低。不脱粒或杀死这些发现强调了感染人类巨细胞病毒的 EVT 的困难。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. 滋养层细胞内的单增李斯特菌 (Lm) 表达大量颗粒溶素，但不杀死宿主细胞。 (GNLY)，一种在细胞毒性颗粒和细胞质中发现的抗菌肽，优先破坏相对于哺乳动物，微生物膜。我们的初步数据表明 dNK 建立了纳米管。细胞质与 EVT 的连接，无需形成传统的免疫突触或脱颗粒，dNK。通过纳米管将 GNLY 转移到 EVT，但不转移其他细胞毒性分子（穿孔素、颗粒酶），否则会杀死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。据我们所知，在维持感染的同时，胎儿和胎盘仍具有耐受性。纳米管免疫功能的证据 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调节滋养层功能。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，识别哪些受感染的母体和胎儿细胞；胎盘中的dNK通过什么机制进行保护；探讨纳米管的作用机制；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。 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，这些外植体和体内研究将研究三种妊娠病原体 - Lm、B 组。链球菌 (GBS) 和弓形虫。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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

NK 细胞受体 NKp46 识别 ER 应激细胞上的外钙网蛋白。

DOI：
发表时间：
2023-04
期刊：
影响因子：
64.8
作者：
Sen Santara, Sumit;Lee, Dian;Crespo, Ângela;Hu, Jun Jacob;Walker, Caitlin;Ma, Xiyu;Zhang, Ying;Chowdhury, Sourav;Meza;Lewandrowski, Mercedes;Zhang, Haiwei;Rowe, Marjorie;McClelland, Arthur;Wu, Hao;Junqueira, Caroline;Lieb
通讯作者：
Lieb

Decidual NK Cells Transfer Granulysin to Selectively Kill Bacteria in Trophoblasts.

蜕膜 NK 细胞转移颗粒溶素以选择性杀死滋养层中的细菌。

DOI：
发表时间：
2020
期刊：
影响因子：
64.5
作者：
Crespo, Ângela C;Mulik, Sachin;Dotiwala, Farokh;Ansara, James A;Sen Santara, Sumit;Ingersoll, Kayleigh;Ovies, Cristian;Junqueira, Caroline;Tilburgs, Tamara;Strominger, Jack L;Lieberman, Judy
通讯作者：
Lieberman, Judy

ELF3 activated by a superenhancer and an autoregulatory feedback loop is required for high-level HLA-C expression on extravillous trophoblasts.

绒毛外滋养细胞上的高水平 HLA-C 表达需要由超级增强子和自动调节反馈环激活的 ELF3。

DOI：
发表时间：
2021
期刊：
影响因子：
11.1
作者：
Li, Qin;Meissner, Torsten B;Wang, Fang;Du, Ziming;Ma, Sai;Kshirsagar, Sarika;Tilburgs, Tamara;Buenrostro, Jason D;Uesugi, Motonari;Strominger, Jack L
通讯作者：
Strominger, Jack L

Human Term Pregnancy Decidual NK Cells Generate Distinct Cytotoxic Responses.

人类足月妊娠蜕膜 NK 细胞产生独特的细胞毒性反应。

DOI：
发表时间：
2020
期刊：
影响因子：
0
作者：
de Mendonça Vieira, Ricardo;Meagher, Ava;Crespo, Ângela C;Kshirsagar, Sarika K;Iyer, Vidya;Norwitz, Errol R;Strominger, Jack L;Tilburgs, Tamara
通讯作者：
Tilburgs, Tamara

Knocking 'em Dead: Pore-Forming Proteins in Immune Defense.

杀死它们：免疫防御中的成孔蛋白。