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10亿的病原体。 呼吸道病毒感染和全球500,000人死亡。流感病毒有很大的大流行潜力， 季节性流行病使人类人口负担沉重，病毒抗药性已发展到所有可用的治疗方法 选择。流感的体液免疫反应是非常重要的，正如中和抗体一样。 理想的疫苗结果。然而，B细胞缺陷小鼠和患有高IgM综合征的人 流感病毒感染，而T细胞缺陷小鼠则不会。因此，B细胞独立的机制保护 对抗流感病毒相关的致命性。我们最近产生了新的令人信服的证据表明IAV感染 在野生型(WT)和T和B细胞缺陷型(Rag1-B)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受体和程序性细胞死亡配体1的表达 和2(PD-L1和PD-L2)对NK细胞的作用。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，而不是PD-1或PD-L2阻断，显著减少IAV相关 杀伤力。IAV/MC-IL10/NK-PD-L1途径在人类中也是保守的，至少在体外是这样：IAV感染 人肺组织来源的单个原代细胞悬液或完整的人肺组织切片诱导MC-IL-10和 NK细胞表达IL-10R、PD-L1和PD-L2。我们发现T细胞还上调IL-10R并调节其PD-R。 1和PD-L1在IAV感染时的表达。试图理解为什么这种调控途径在进化上 保守地说，我们发现细胞毒性T淋巴细胞(CTL)是IAV诱导的主要因素 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-10R，PD-1，PD- L1，或PD-L2，在IAV清除后形成长期的免疫渗透和免疫病理。我们假设 流感病毒诱导的MC-IL-10紧密平衡了杀菌免疫和有害的免疫病理 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 表达和信号传递。我们的发现既新颖又令人惊讶。PD/PD-L通路的诱导 通常与癌症或慢性感染中的淋巴细胞衰竭(通过T细胞表达的PD-1)有关。 然而，对IL-10和PD-L1信号如何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信号转导如何 调节NK和T细胞功能及其在流感病毒清除和肺部病理中的作用 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论基础 开发新的治疗方法，在增强抗病毒免疫反应的同时防止有害的 免疫病理学。