Manipulating natural host immunoregulation via IDO during viral Infection

描述(申请人提供)：目的是阐明流感病毒感染和流感疫苗对涉及吲哚胺2，3双加氧酶(IDO)表达的自然宿主T细胞调节机制的影响。IDO介导的T细胞抑制有助于临床相关的慢性炎症综合征，包括肿瘤生长、自身免疫、过敏和移植物抗宿主疾病。IDO活性阻断了怀孕期间T细胞对胎儿组织的反应，IDO过表达提高了移植的存活率。流感感染导致肺部IDO活性急剧增加，IDO活性促进肺炎等继发性感染。我们假设IDO减弱了对流感感染和预防性疫苗的效应者T细胞免疫反应。这种作用可能会促进组织愈合，但可能会削弱T细胞对流感感染的反应，阻碍一代保护性免疫，并增加继发感染的风险。某些浆细胞样树突状细胞(PDC)表达IDO可抑制炎症部位的T细胞反应。在初步研究中，我们发现化学诱导的皮肤炎症诱导皮肤引流淋巴结(DLN)中的PDCs表达IDO。IDO+PDCs获得了强大的T细胞调节功能，阻止了T细胞的克隆性增殖，并触发了调节性T细胞(Tregs)获得抑制活性。在提出的研究中，我们将使用新的小鼠品系和病毒载体在已建立的小鼠流感感染模型中消融IDO，并评估消融IDO对流感特异性免疫、记忆生成和感染动力学的影响。我们将鉴定表达IDO的肺细胞，以及刺激IDO的炎症信号(目标1)。同时，我们将阐明肺IDO+细胞对流感特异性效应T细胞和记忆T细胞的影响(目标2)。相关研究将集中在消融IDO对流感疫苗预防和疗效的影响(目标3)，以及加强治疗性疫苗接种以对抗流感感染的新方法(目标4)。拟议研究的完成将提高对IDO在调节T细胞对流感的反应中的作用的理解，并将为改进预防流感的治疗干预创造新的机会。

DESCRIPTION (provided by applicant): The objective is to elucidate the effects of influenza (flu) virus infection and flu vaccines on a natural host T cell regulatory mechanism involving expression of indoleamine 2,3 dioxygenase (IDO). IDO-mediated T cell suppression contributes to chronic inflammatory syndromes of clinical relevance, including tumor growth, autoimmune, allergic, and graft-versus-host diseases. IDO activity blocks T cell responses to fetal tissues during pregnancy, and IDO over-expression enhances transplant survival. Flu infection induces a dramatic increase in IDO activity in lungs, and IDO activity facilitates secondary infections such as pneumonia. We hypothesize that IDO attenuates effector T cell immune responses to flu infection and to preventative vaccines. Such effects may promote tissue healing, but may blunt T cell responses to flu infection, impede generation protective immunity, and increase the risk of secondary infections. IDO expression by some plasmacytoid dendritic cells (pDCs) inhibits T cell responses at sites of inflammation. In preliminary studies we show that chemically-induced skin inflammation induced pDCs in skin draining lymph nodes (dLNs) to express IDO. IDO+ pDCs acquired potent T cell regulatory functions that blocked T cell clonal expansion, and triggered regulatory T cells (Tregs) to acquire suppressor activity. In studies proposed, we will employ new mouse strains and viral vectors to ablate IDO in an established murine flu infection model, and assess the effects of IDO ablation on flu-specific immunity, memory generation, and infection kinetics. We will identify lung cells expressing IDO, and inflammatory signals that stimulate IDO (Aim 1). In parallel, we will elucidate the effects of lung IDO+ cells on flu-specific effector and memory T cells (Aim 2). Related studies will focus on the effects of IDO ablation on flu vaccine prophylaxis and efficacy (Aim 3), and a novel means to enhance therapeutic vaccination to combat flu infections (Aim 4). Completion of studies proposed will improve understanding of the role of IDO in regulating T cell responses to flu, and will create novel opportunities for improving therapeutic interventions protect against flu.