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

描述（由申请人提供）：西尼罗河病毒（WNV）是一种病媒传播的病原体，自1999年以来每年在北美爆发病毒性脑炎。在超过30%的确诊西尼罗河病毒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。目前还没有人类疫苗。因此，重要的是要了解的因素有助于发展的长期持久的保护性免疫，特别是在潜在的易感宿主。34 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细胞对于早期控制WNV传播是重要的，2）TCR 4/（34 T细胞缺陷）小鼠具有降低的CD 8 + T细胞记忆应答，并且更容易继发WNV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受到WNV诱导的脑炎。34老年小鼠的T细胞对WNV感染的反应比年轻小鼠的反应慢得多。这表明老年小鼠中34 T细胞的功能障碍有助于增强宿主对WNV诱导的脑炎的易感性。老年人免疫力下降是导致病原体感染风险增加的重要因素。本申请的总体目标是检查34 T细胞在针对WNV的宿主适应性免疫中的作用。具体来说，我们假设34 T细胞是至关重要的记忆T细胞的发展后，西尼罗河病毒的挑战;功能障碍的34 T细胞在老年小鼠导致对西尼罗河病毒的适应性免疫缺陷。在具体目标1中，我们将进一步确定34 T细胞在针对WNV的宿主适应性免疫中的作用。我们将描述不同发育阶段的CD 8 + T细胞应答，并评估TCR 4-/-小鼠中的CD 4 + T细胞记忆应答。在具体目标2中，我们将试图剖析34 T细胞调节宿主获得性免疫的潜在机制。将检查在WNV感染期间34 T细胞和其他免疫细胞之间的相互作用。在具体目标3中，我们将确定老年小鼠中34 T细胞的功能障碍是否导致针对WNV的有缺陷的适应性免疫。从这项研究中获得的信息不仅将提高我们对宿主免疫力的理解，对西尼罗河病毒，但也将提供关键的基本见解，在黄病毒疫苗开发的新策略。西尼罗河病毒（WNV）已成为日益严重的公共卫生问题。在超过30%的确诊西尼罗河病毒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。目前还没有人类疫苗。重要的是要了解有助于形成持久保护性免疫力的因素，特别是在潜在的易感宿主中。本申请的总体目标是检查34 T细胞在针对WNV的适应性免疫中的作用。我们预计，从这项研究中获得的信息不仅将提高我们对宿主免疫力的理解对西尼罗河病毒，但也将提供关键的基本见解，在黄病毒疫苗开发的新策略。

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.