Novel mechanisms regulating immunity to respiratory virus infection

调节呼吸道病毒感染免疫力的新机制

• 批准号: 10931141
• 负责人: Silke Paust
• 金额: $ 91.35万
• 依托单位: JACKSON LABORATORY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-02 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10931141
• 关键词: Novel; mechanisms; regulating; immunity; respiratory

Influenza viruses are rapidly mutating RNA viruses and the causative agent of about one billion annual respiratory virus infections and 500,000 deaths worldwide. Influenza virus has significant pandemic potential, seasonal epidemics burden the human population, and viral resistance has developed to all available treatment options. Much emphasis is placed on the humoral immune response to influenza, as neutralizing antibodies are the desired vaccine outcome. However, B cell-deficient mice and humans with hyper-IgM syndrome clear influenza virus infections, while T cell-deficient mice do not. Thus, B cell-independent mechanisms protect against influenza virus-related lethality. We recently generated novel and compelling evidence that IAV infection triggers lung mast cells (MCs) to produce IL-10 (MC-IL-10) in wild type (WT) and T- and B-cell deficient (Rag1- KO) mice. MC-IL-10 induces the expression of the IL-10 receptor (IL-10R) and programmed cell death ligands 1 and 2 (PD-L1 and PD-L2) on Natural Killer (NK) cells. Notably, in Rag1-KO mice, where NK cells are the sole virus-fighting lymphocytes, PD-L1 blockade, but not PD-1 or PD-L2 blockade, significantly reduces IAV-related lethality. The IAV/MC-IL10/NK-PD-L1 pathway is also conserved in humans, at least in vitro: IAV infection of human-lung tissue-derived single-primary-cell suspensions or intact human lung tissue slices elicit MC-IL-10 and NK cell-expressed IL-10R, PD-L1, and PD-L2. We found T cells also upregulate IL-10R and modulate their PD- 1 and PD-L1 expression upon IAV infection. Seeking to understand why this regulatory pathway is evolutionarily conserved, we found cytotoxic T lymphocytes (CTLs) implicated as the main contributors to IAV induced immunopathology. Indeed, IL-10-KO/Rag-WT mice, whose NK and T cells do not upregulate IL-10R, PD-1, PD- L1, or PD-L2, develop prolonged immune infiltration and immunopathology after IAV clearance. We hypothesize that influenza virus-induced MC-IL-10 balances sterilizing immunity and harmful immunopathology, tightly regulating NK and T cell functions through their MC-IL-10 induced PD-1 (CTLs) and PD-L1 (NK cells and CTLs) expression and signaling. Our findings are novel and surprising. The induction of the PD/PD-L pathway is generally associated with lymphocyte exhaustion (via T cell expressed PD-1) in cancer or chronic infection. However, little is known about how IL-10 and PD-L1 signals to modulate lymphocyte functions, especially in acute viral illness. To address this knowledge gap, we propose to determine how IL-10 and PD-L1-signaling regulates NK and T cell functions and their contributions to viral clearance vs. lung pathology upon influenza virus infection. The knowledge gained will be highly relevant to human health. Our data will provide the rationale to develop novel therapeutics augmenting the antiviral immune response while preventing detrimental immunopathology.

流感病毒是一种快速变异的 RNA 病毒，是每年约 10 亿流感病毒的病原体 全球有呼吸道病毒感染和 50 万人死亡。流感病毒具有巨大的大流行潜力， 季节性流行病给人类带来了负担，病毒对所有可用的治疗都产生了耐药性 选项。人们非常重视对流感的体液免疫反应，因为中和抗体 期望的疫苗结果。然而，B 细胞缺陷小鼠和患有高 IgM 综合征的人类明确 流感病毒感染，而 T 细胞缺陷小鼠则不会。因此，B 细胞独立机制可以保护 对抗流感病毒相关的致死率。我们最近生成了新的、令人信服的证据表明 IAV 感染 在野生型 (WT) 以及 T 细胞和 B 细胞缺陷型 (Rag1-) 中触发肺肥大细胞 (MC) 产生 IL-10 (MC-IL-10) KO）小鼠。 MC-IL-10 诱导 IL-10 受体 (IL-10R) 和程序性细胞死亡配体 1 的表达 和 2（PD-L1 和 PD-L2）针对自然杀伤 (NK) 细胞。值得注意的是，在 Rag1-KO 小鼠中，NK 细胞是唯一的 抗病毒淋巴细胞、PD-L1 阻断（但不是 PD-1 或​​ PD-L2 阻断）可显着减少 IAV 相关性 杀伤力。 IAV/MC-IL10/NK-PD-L1 通路在人类中也是保守的，至少在体外：IAV 感染 人肺组织来源的单原代细胞悬浮液或完整人肺组织切片可诱导 MC-IL-10 和 NK 细胞表达 IL-10R、PD-L1 和 PD-L2。我们发现 T 细胞也上调 IL-10R 并调节其 PD- IAV 感染后的 1 和 PD-L1 表达。寻求理解为什么这种监管途径是进化的 保守的，我们发现细胞毒性 T 淋巴细胞 (CTL) 是 IAV 诱导的主要贡献者 免疫病理学。事实上，IL-10-KO/Rag-WT 小鼠的 NK 和 T 细胞不会上调 IL-10R、PD-1、PD- IAV 清除后，L1 或 PD-L2 会产生长期的免疫浸润和免疫病理学。我们假设 流感病毒诱导的 MC-IL-10 紧密平衡杀菌免疫和有害免疫病理学 通过 MC-IL-10 诱导 PD-1 (CTL) 和 PD-L1（NK 细胞和 CTL）调节 NK 和 T 细胞功能 表达和信号传导。我们的发现新颖且令人惊讶。 PD/PD-L 途径的诱导是 通常与癌症或慢性感染中的淋巴细胞耗竭（通过 T 细胞表达 PD-1）有关。 然而，人们对 IL-10 和 PD-L1 如何发出信号来调节淋巴细胞功能知之甚少，尤其是在 急性病毒性疾病。为了解决这一知识差距，我们建议确定 IL-10 和 PD-L1 信号传导如何 调节 NK 和 T 细胞功能及其对流感病毒清除与肺部病理学的贡献 病毒感染。获得的知识将与人类健康高度相关。我们的数据将提供理由 开发新的疗法，增强抗病毒免疫反应，同时预防有害的 免疫病理学。