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，每年约有10亿人感染流感病毒。 呼吸道病毒感染和全球50万人死亡。流感病毒具有很大的流行潜力， 季节性流行病给人类带来负担，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，因为中和抗体是 所需的疫苗效果。然而，B细胞缺陷小鼠和高IgM综合征的人清楚， 流感病毒感染，而T细胞缺陷小鼠则没有。因此，不依赖于B细胞的机制保护了 对抗流感病毒相关的致命性。我们最近发现了新的令人信服的证据， 在野生型（WT）和T-和B-细胞缺陷型（Rag 1-Rag 2）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-10 R）和程序性细胞死亡配体1的表达 和2（PD-L1和PD-L2）对自然杀伤（NK）细胞的作用。值得注意的是，在Rag 1-KO小鼠中，NK细胞是唯一的细胞， 抗病毒淋巴细胞，PD-L1阻断，而不是PD-1或PD-L2阻断，显著降低了IAV相关的 杀伤力IAV/MC-IL 10/NK-PD-L1途径在人类中也是保守的，至少在体外是这样： 人肺组织来源的单原代细胞悬浮液或完整的人肺组织切片引发MC-IL-10， NK细胞表达IL-10 R、PD-L1和PD-L2。我们发现T细胞也上调IL-10 R并调节其PD-1。 1和PD-L1表达。试图理解为什么这种调节途径在进化上 保守，我们发现细胞毒性T淋巴细胞（CTL）牵连的主要贡献者IAV诱导 免疫病理学事实上，IL-10-KO/Rag-WT小鼠，其NK和T细胞不上调IL-10 R、PD-1、PD-2、PD-3、PD-4、PD-5、PD-6、PD-7、PD-8、PD-9、PD-10、PD-11、PD-12、PD-13、PD-14、PD-15、PD-16、PD-17、PD-18、PD-19、PD L1或PD-L2在IAV清除后发展出延长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能够紧密平衡杀菌免疫和有害的免疫病理学， 通过MC-IL-10诱导的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。我们的发现是新颖和令人惊讶的。PD/PD-L通路的诱导是 通常与癌症或慢性感染中的淋巴细胞耗竭（通过T细胞表达的PD-1）相关。 然而，关于IL-10和PD-L1信号如何调节淋巴细胞功能，特别是在淋巴细胞中， 急性病毒性疾病为了解决这一知识缺口，我们建议确定IL-10和PD-L1信号传导 调节NK和T细胞功能及其对流感病毒清除与肺病理学的贡献 病毒感染。所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 开发新的治疗方法，增强抗病毒免疫反应，同时防止有害的 免疫病理学