Gammadelta T cell Regulation of Adaptive Immunity in West Nile Virus Infection

描述（由申请人提供）：西尼罗病毒（WNV）是一种媒介传播的病原体，自1999年以来在北美每年暴发病毒性脑炎。在30%以上的西尼罗河病毒确诊病例中观察到严重的神经系统疾病（脑炎或死亡），老年人和免疫功能低下患者的发病率更高。目前还没有人用疫苗。因此，了解促进长期保护性免疫发展的因素，特别是在潜在易感宿主中，是很重要的。34个T细胞，非经典T细胞亚群，参与微生物感染的早期控制。在最近发表的两项研究中，我们已经表明1)34 T细胞对西尼罗河病毒传播的早期控制很重要，2)TCR4 / （34 T细胞缺陷）小鼠CD8+ T细胞记忆反应降低，更容易继发性西尼罗河病毒感染。此外，我们的初步数据显示，老年小鼠比年轻小鼠更容易患西尼罗河病毒引起的脑炎。老年小鼠的T细胞对西尼罗河病毒感染的反应比年轻小鼠慢得多。这表明老年小鼠34个T细胞功能障碍有助于增强宿主对西尼罗河病毒引起的脑炎的易感性。老年人免疫力的下降是病原体感染风险增加的一个重要因素。该应用程序的总体目标是检查34 T细胞在宿主对西尼罗河病毒的适应性免疫中的作用。具体来说，我们假设34个T细胞对WNV攻击后记忆T细胞的发育至关重要；老年小鼠34个T细胞功能障碍导致对西尼罗河病毒的适应性免疫缺陷。在特异性目标1中，我们将进一步确定34种T细胞在宿主抗西尼罗河病毒适应性免疫中的作用。我们将描述不同发育阶段的CD8+ T细胞反应，并评估TCR4-/-小鼠的CD4+ T细胞记忆反应。在特异性目标2中，我们将尝试剖析34个T细胞调节宿主适应性免疫的潜在机制。将检测34种T细胞与其他免疫细胞在西尼罗河病毒感染期间的相互作用。在特异性目的3中，我们将确定老年小鼠34个T细胞的功能障碍是否会导致对西尼罗河病毒的适应性免疫缺陷。从这项研究中获得的信息不仅将增强我们对宿主对西尼罗河病毒免疫的理解；但也将为黄病毒疫苗开发的新策略提供关键的基本见解。公共卫生启示：西尼罗河病毒（WNV）已成为一个日益严重的公共卫生问题。在30%以上的西尼罗河病毒确诊病例中观察到严重的神经系统疾病（脑炎或死亡），老年人和免疫功能低下患者的发病率更高。目前还没有人用疫苗。重要的是要了解促进长期保护性免疫发展的因素，特别是在潜在易感宿主中。本应用程序的总体目标是检查34 T细胞在抗西尼罗河病毒适应性免疫中的作用。我们期望从这项研究中获得的信息不仅可以增强我们对宿主对西尼罗河病毒免疫的理解；但也将为黄病毒疫苗开发的新策略提供关键的基本见解。

DESCRIPTION (provided by applicant): West Nile virus (WNV), a vector-borne pathogen, has resulted in annual outbreaks of viral encephalitis in North America since 1999. Severe neurological disease (encephalitis or death) has been observed in over 30% of the confirmed WNV cases with a higher frequency in the elderly and immunocompromised patients. Human vaccines are not available yet. Thus, it is important to understand factors contributing to the development of long-lasting protective immunity, especially in the potentially susceptible host. 34 T cells, the non-classical T cell subsets, are involved in the early control of microbial infection. In two recently published studies, we have shown that 1) 34 T cells are important for early control of WNV dissemination and that 2) TCR4 / (34 T cell deficient) mice have reduced CD8+ T cell memory response and are more susceptible to secondary WNV infection. Moreover, our preliminary data show that aged mice are more susceptible to WNV induced encephalitis than young mice. 34 T cells of aged mice respond to WNV infection in a much slower and reduced manner than those of young mice. This suggests that the dysfunction of 34 T cells in aged mice contributes to the enhanced host susceptibility to WNV induced encephalitis. The decline in immunity in the elderly is a significant contributor to the increased risk of pathogen infection. The overall goal of this application is to examine the role of 34 T cells in host adaptive immunity against WNV. Specifically, we hypothesize that 34 T cells are crucial for the development of memory T cells following WNV challenge; dysfunction of 34 T cells in aged mice leads to a defective adaptive immunity against WNV. In Specific aim 1, we will further define the role of 34 T cells in host adaptive immunity against WNV. We will characterize CD8+ T cell response at different stages of development and assess CD4+ T cell memory response in TCR4-/- mice. In Specific aim 2, we will attempt to dissect the underlying mechanisms by which 34 T cells regulate host adaptive immunity. The interactions between 34 T cells and other immune cells during WNV infection will be examined. In Specific aim 3, we will determine whether the dysfunction of 34 T cells in aged mice leads to a defective adaptive immunity against WNV. Information obtained from this study will not only enhance our understanding of host immunity against WNV; but also will provide critical basic insights for new strategies in flavivirus vaccine development. PUBLIC HEALTH REVELENCE: West Nile virus (WNV) has become an increasing public health concern. Severe neurological disease (encephalitis or death) has been observed in over 30% of the confirmed WNV cases with a higher frequency in the elderly and immunocompromised patients. Human vaccines are not available yet. It is important to understand factors contributing to the development of long-lasting protective immunity, especially in the potentially susceptible host. The overall goal of this application is to examine the role of 34 T cells in adaptive immunity against WNV. We anticipate information obtained from this study will not only enhance our understanding of host immunity against WNV; but also will provide critical basic insights for new strategies in flavivirus vaccine development.