Identification of lung resident innate lymphocytes that specifically protect neonates from SARS-CoV-2 infections

摘要 免疫调节粘膜屏障的发展和维持是婴儿健康的关键过程， 由于免疫前哨活性失衡会导致肺、皮肤和肠道炎症。中心是 粘膜组织动态平衡是产生3型细胞因子的淋巴细胞(T3L)。在小鼠中，胎源性γδTcR+T3L 名为Tγδ17的细胞主要调节皮肤的动态平衡，并介导对流感感染的保护性免疫 出生后不久。Tγδ17细胞被归类为先天淋巴细胞，因为它们的效应功能是在 胸腺在迁移到肺部和皮肤之前。在那里，Tγδ17细胞对环境做出快速反应 提示加强组织屏障和协调病原体清除。Tγδ17细胞是这一类的代表 包括多种细胞类型的先天T3L(IT3L)，它们的主要区别是如何识别 环境线索以及它们在什么年龄的组织中起主导作用。SARS-CoV-2感染是 对老年人尤其危险，而儿童对重度新冠肺炎具有抵抗力。这项探索性的建议 将测试新生儿肺Tγδ17细胞或其他iT3L细胞对SARS-CoV-2具有保护作用的假设。 这一假说的理论基础建立在四个基本观察之上：1.感染SARS-CoV-2的儿童产生 T3反应，而老年人只表现出沉默的反应；2.小鼠肺Tγδ17细胞保护 脓毒症，一种类似严重新冠肺炎的疾病；3.新生儿Tγδ17细胞保护肺组织免受 随着年龄的增长，Tγδ17细胞会发生磨损。由此可见，老年严重的新冠肺炎 部分原因是随着年龄的增长，肺iT3L保护功能受损。该项目将建立T3L成分 以及新生儿和成人感染SARS冠状病毒前后的激活状态，识别肺iT3L亚群(S) 它主要赋予新生儿对SARS-CoV-2感染的抵抗力，并决定饮食和感染 病史影响Tγδ17细胞介导的对呼吸道感染的肺保护反应。通过了解如何 年轻人成功应对SARS-CoV-2新洞察为什么老年人会屈服于新冠肺炎 获得。这反过来将为对抗新冠肺炎的新疗法提供线索。

Summary Immunological regulation of mucosal barrier development and maintenance is a critical process for infant health, as imbalances in immune sentinel activity can lead to lung, skin and gut inflammatory diseases. Central to the mucosal tissue homeostasis are Type 3 cytokine producing lymphocytes (T3L). In mice, fetal-origin γδTCR+ T3L called Tγδ17 cells dominantly regulate skin homeostasis and mediate protective immunity to influenza infections soon after birth. Tγδ17 cells are classified as innate lymphocytes as their effector function is programmed in the thymus before they migrate to populate the lung and skin. There, Tγδ17 cells respond rapidly to environmental cues to fortify the tissue barriers and coordinate pathogen clearance. Tγδ17 cells are representative of the class of innate T3L (iT3L) that include multiple cell types, whose major distinctions are how they recognize environmental cues and at what age of tissues they functionally dominate. SARS-CoV-2 infections are particularly dangerous for the elderly, while children are resistant to severe COVID-19. This exploratory proposal will test the hypothesis that neonatal lung Tγδ17 cells, or other iT3L, confer protection against SARS-CoV-2. Rationale for the hypothesis is built on four foundational observations: 1. SARS-CoV-2 infected children generate T3 responses while the aged only show muted responses, if at all; 2. Murine lung Tγδ17 cells protect against sepsis, a disease with similarity to severe COVID-19; 3. Neonatal Tγδ17 cells protect lung tissues against Influenza in mice; and 4. Attrition of Tγδ17 cells occurs with aging. It follows that the severe COVID-19 in elderly are in part caused by compromised lung iT3L protection with age. This project will establish T3L composition and activation status pre- and post- SARS-CoV-2 infection in neonates and adults, identify lung iT3L subset(s) that dominantly confer resistance to SARS-CoV-2 infections in neonates, and determine how diet and infection history impacts Tγδ17 cell-mediated lung protective responses to respiratory infections. By understanding how the young successfully respond to SARS-CoV-2 new insights into why the aged succumb to COVID-19 can be obtained. This in turn will provide leads into novel therapeutics against COVID-19.