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

描述(申请人提供)：西尼罗河病毒(WNV)是一种媒介传播的病原体，自1999年以来每年在北美导致病毒性脑炎的爆发。在确诊的西尼罗河病毒病例中，超过30%的人患有严重的神经系统疾病(脑炎或死亡)，其中老年人和免疫功能低下的患者发病率较高。目前还没有人用疫苗。因此，重要的是要了解有助于发展长期保护性免疫的因素，特别是在潜在的易感宿主中。34T细胞是非经典T细胞亚群，参与了微生物感染的早期控制。在最近发表的两项研究中，我们发现1)34个T细胞对早期控制西尼罗河病毒的传播很重要，2)TCR4/(34个T细胞缺陷)小鼠CD8+T细胞记忆反应降低，更容易受到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感染西尼罗河病毒引起的脑炎。老年小鼠的34T细胞对西尼罗河病毒感染的反应比青年小鼠慢得多，而且反应减弱。提示老年小鼠体内34T细胞的功能障碍与宿主对西尼罗河病毒所致脑炎的易感性增加有关。老年人免疫力下降是病原体感染风险增加的一个重要因素。这项应用的总体目标是研究34个T细胞在宿主对西尼罗河病毒的获得性免疫中的作用。具体地说，我们假设34个T细胞对西尼罗河病毒攻击后记忆T细胞的发育至关重要；老年小鼠34个T细胞功能障碍导致针对西尼罗河病毒的获得性免疫缺陷。在具体目标1中，我们将进一步明确34T细胞在宿主抗西尼罗病毒获得性免疫中的作用。我们将表征CD8+T细胞在不同发育阶段的反应，并评估TCR4-/-小鼠的CD4+T细胞记忆反应。在特定的目标2中，我们将试图剖析34T细胞调节宿主获得性免疫的潜在机制。将检查34个T细胞与其他免疫细胞在西尼罗河病毒感染过程中的相互作用。在具体目标3中，我们将确定老年小鼠中34个T细胞的功能障碍是否导致针对西尼罗河病毒的获得性免疫缺陷。从这项研究中获得的信息不仅将加强我们对针对西尼罗河病毒的宿主免疫的了解，还将为黄病毒疫苗开发的新策略提供关键的基本见解。公共卫生报道：西尼罗河病毒(WNV)已成为日益严重的公共卫生问题。在确诊的西尼罗河病毒病例中，超过30%的人患有严重的神经系统疾病(脑炎或死亡)，其中老年人和免疫功能低下的患者发病率较高。目前还没有人用疫苗。重要的是要了解有助于发展长期保护性免疫的因素，特别是在潜在的易感宿主中。这项应用的总体目标是研究34个T细胞在针对西尼罗河病毒的获得性免疫中的作用。我们预计，从这项研究中获得的信息不仅将加强我们对针对西尼罗河病毒的宿主免疫的了解，还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.