IL-17 regulation of type-1 immunity in chronic viral infection

摘要 在没有杀死宿主的情况下成功逃脱清除的病毒会建立慢性感染。 然而，随着时间的推移，未解决的低度炎症会导致发病率，包括发育 癌症。如何适当地调节对慢性感染的免疫反应而不进一步 损害宿主是一项重大的临床挑战。第17类豁免权由 胞外细菌和真菌控制屏障上的驻留微生物群和入侵病原体 表面，并促进组织修复。Th17细胞作为人类免疫缺陷病毒的驱动力受到了极大关注 慢性自身免疫性疾病中的炎症。然而，关于这一角色的数据却很少 对病毒感染的17型反应。在这里，我们雇用了性格精良的 模型感染，LCMV克隆13，以测试IL-17在慢性病毒感染中的作用。IL-17是 在转换到慢性感染阶段期间系统性增加。使用遗传和 抗体介导的IL-17的阻断，我们的数据意外地揭示了IL-17调节Th1和 巨细胞病毒感染过程中CD8T细胞的活化、耗竭及免疫病理变化我们有 确认称为成纤维细胞网状细胞(FRC)的淋巴基质细胞是关键的中介细胞 IL-17在次级淋巴组织中的作用。基因表达分析与抗体介导 阻断支持过量的IFNG在驱动T细胞衰竭和免疫病理中的作用。这些 意想不到的发现导致了我们的中心假设，即IL-17在 慢性感染通过限制抗病毒T细胞IFNG介导的耗竭和免疫病理学。这 项目旨在剖析我们已确定的在此 通过探索IL-17的来源探讨慢性感染中未知的免疫调节途径 (Aim 1)，作为IL-17靶点的LN基质细胞(Aim 2)和IFNG介导的力竭和 缺乏IL-17信号的免疫病理学(目标3)。这些数据加在一起将定义一部小说 而此前未探索的轴通过基质细胞中的IL-17信号来调节IFNG- 介导性病理，揭示慢性阻塞性肺疾病未来治疗干预的新机遇 被感染的人。

ABSTRACT Viruses that successfully evade clearance without killing the host establish chronic infection. However, unresolved low-grade inflammation causes morbidity over time, including development of cancers. How to appropriately modulate immune responses to chronic infection without further damaging the host represents a major clinical challenge. Type-17 immunity is invoked by extracellular bacteria and fungi to control resident microbiota and invading pathogens at barrier surfaces, and to promote tissue repair. Th17 cells have received much attention as drivers of inflammation in chronic autoimmune diseases. However, there are sparse data regarding the role of type-17 responses in response to viral infection. Here we have employed the well-characterized model infection, LCMV clone 13, to test the role of IL-17 during chronic viral infection. IL-17 was increased systemically during the switch to the chronic phase of infection. Using genetic and antibody-mediated blockade of IL-17, our data unexpectedly reveal that IL-17 regulates Th1 and CD8+ T cell activation, exhaustion and immunopathology during LCMV infection. We have identified lymphoid stromal cells known as fibroblastic reticular cells (FRC) as key intermediaries of IL-17 effects in secondary lymphoid tissues. Gene expression analysis and antibody-mediated blockade support a role for excess IFNg in driving T cell exhaustion and immunopathology. These unexpected findings lead to our central hypothesis that IL-17 has an immunoregulatory role during chronic infection by limiting antiviral T cell IFNg-mediated exhaustion and immunopathology. This project is designed to dissect the key elements that we have identified to be required in this unexplored immunoregulatory pathway in chronic infection by probing the source of critical IL-17 (aim 1), LN stromal cells as targets of IL-17 (aim 2) and IFNg-mediated effects on exhaustion and immunopathology in absence of IL-17 signaling (aim 3). Together these data will define a novel and previously unexplored axis operating through IL-17 signaling in stromal cells to regulate IFNg- mediated pathology, revealing new opportunities for future therapeutic intervention in chronically infected people.