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; 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.

流感病毒正在迅速突变RNA病毒，每年约十亿 全球呼吸道病毒感染和500,000例死亡。流感病毒具有巨大的大流行潜力， 季节性流行病负担人口负担，病毒抗性已发展为所有可用治疗 选项。由于中和抗体是对流感的体液免疫反应，因此非常重视体液的免疫反应 所需的疫苗结果。然而，B细胞缺陷的小鼠和患有超基因综合征的人类清除 流感病毒感染，而T细胞缺陷小鼠则没有。因此，B细胞独立的机制保护 反对与流感病毒相关的杀伤力。我们最近产生了IAV感染的新颖和令人信服的证据 触发肺肥大细胞（MCS）以野生型（WT）以及T-和B细胞缺乏（RAG1--- 小鼠。 MC-IL-10诱导IL-10受体（IL-10R）和程序性细胞死亡配体的表达1 自然杀手（NK）细胞上的2（PD-L1和PD-L2）。值得注意的是，在rag1-ko小鼠中，其中nk细胞是鞋底 抗病毒淋巴细胞，PD-L1阻滞，但没有PD-1或PD-L2阻滞，显着降低了与IAV相关的 致死性。 IAV/MC-IL10/NK-PD-L1途径在人类中也是保守的，至少在体外：IAV感染 人肺组织衍生的单纤维细胞悬浮液或完整的人肺组织切片会引起MC-IL-10和 NK细胞表达的IL-10R，PD-L1和PD-L2。我们发现T细胞还上调IL-10R并调节其PD- IAV感染后的1和PD-L1表达。试图理解为什么这种监管途径在进化上是 保守的，我们发现细胞毒性T淋巴细胞（CTL）涉及IAV诱导的主要因素 免疫病理学。实际上，IL-10-ko/rag-wt小鼠的NK和T细胞不会上调IL-10R，PD-1，PD- L1或PD-L2在IAV清除后会长期产生长时间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平衡灭菌免疫和有害免疫病理学，紧密 通过其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。我们的发现是新颖而令人惊讶的。 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衰竭（通过TEREDES PD-1）相关。 但是，关于如何调节淋巴细胞功能的IL-10和PD-L1信号知之甚少，尤其是在 急性病毒疾病。为了解决这一知识差距，我们建议确定IL-10和PD-L1信号如何 调节NK和T细胞功能及其对病毒清除与肺病理学对流感的贡献 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 开发新型治疗学，增强抗病毒免疫反应，同时预防有害 免疫病理学。