Mechanisms of dysregulated immunity with aging

描述(申请人提供)：病毒感染导致老年人的发病率和死亡率高于年轻人。根据实验和临床研究，这种疾病负担被认为是由于免疫反应下降所致。然而，在上一个奖项周期的支持下，我们发表的工作对这一范式提出了挑战，因为我们发现，老年小鼠在病毒感染期间表现出失调的免疫反应，导致免疫病理。这种失调包括由自然杀伤T细胞(NKT)产生的过度的IL-17反应，对病原体快速反应的先天免疫淋巴细胞，以及由浆细胞样树突状细胞(PDCs)产生的I型干扰素(干扰素)缺陷反应，后者是帮助病毒清除的哨兵免疫细胞。这种缺陷的病毒清除与增龄的IL-17反应协同作用，导致严重的肝脏炎症和死亡。在非致死性全身性病毒感染期间，NKT细胞过度的炎症反应(即产生IL-6)与pDC的I型干扰素反应缺陷相结合，导致炎症环境使适应性免疫CD4+T细胞向产生IL-17的表型倾斜。我们还观察到，在其他病毒感染中，例如在局限性流感肺部感染中，IL-17反应与I型IFN缺陷相结合。在这里，我们建议通过使用小鼠模型来研究免疫反应随年龄增长而失调的潜在的细胞和分子机制，以确定1)在系统性疱疹病毒随年龄增长的感染过程中，NKT细胞过度的炎症反应与缺陷的PDC反应是否是产生IL-17抗病毒的CD4+T细胞的关键；以及2)衰老的NKT细胞的过度的IL-17反应与pDC的I型干扰素反应受损是否也在流感病毒肺部感染过程中诱导免疫病理。我们的工作将大大不同于该领域的主流研究，并可能导致新的抗炎疗法，以提高对病毒感染的免疫力随着年龄的增长。

DESCRIPTION (provided by applicant): Viral infections induce higher morbidity and mortality in older people than in younger individuals. Based on both experimental and clinical studies, this disease burden is thought to be due to declining immune responses. However, our published work supported by the last cycle of the award challenges this paradigm as we found that older mice exhibit dysregulated immune responses during viral infection that induce immune pathology. This dysregulation consists of exaggerated IL-17 responses produced by natural killer T (NKT) cells, innate immune lymphocytes that respond rapidly to pathogens, coupled to defective type I interferon (IFN) responses by plasmacytoid dentritic cells (pDCs), sentinel immune cells that aid viral clearance. This defective viral clearance synergizes with the age-elevated IL-17 responses leading to severe liver inflammation and death. During non-lethal systemic viral infections, exaggerated inflammatory responses (i.e., IL-6 production) by NKT-cells coupled with defective type I IFN responses by pDCs induce an inflammatory environment that skews adaptive immune CD4+ T cells to an IL-17 producing phenotype. We have also observed the age-elevated IL-17 response coupled to defective type I IFNs in other viral infections such as in localized influenza lung infections. Here, we propose to study the underlying cellular and molecular mechanisms for dysregulation of immune responses with aging by using murine models to determine 1) if exaggerated inflammatory responses by NKT cells coupled to defective pDC responses are critical for the generation of IL-17 anti-viral CD4+ T cells during systemic herpes viral infections with aging; and 2) whether exaggerated IL-17 responses by aged NKT cells coupled with impaired type I IFN responses by pDCs also induce immune pathology during influenza viral lung infection. Our work will greatly differ from mainstream research in the field and may lead to novel anti-inflammatory therapies to improve immunity to viral infections with aging.