Immunopathology mediated by RSV-specific CD4 T cells

描述（由申请人提供）：呼吸道合胞病毒（RSV）是婴幼儿病毒性下呼吸道感染的主要原因。此外，RSV在老年人和免疫功能低下的个体中引起严重疾病。RSV免疫与自然感染后疾病增强和肺嗜酸性粒细胞增多有关，这被认为是由旺盛的记忆CD4 Th2反应引起的。因此，目前还没有批准的RSV疫苗，针对预防疫苗相关疾病的详细研究是开发安全有效疫苗的必要第一步。RSV感染的BALB/c小鼠模型忠实地模拟了人类呼吸道疾病，包括广泛的肺部炎症和损伤的发展，肺嗜酸性粒细胞增多，以及先前接种福尔马林灭活(FI)-RSV或表达附着(G)糖蛋白的重组痘痘病毒（vv）免疫的小鼠的疾病增强。分泌Th2细胞因子的记忆性CD4 T细胞对这种反应是必要的，因为它们的消耗消除了嗜酸性粒细胞。最近的研究表明，RSV特异性CD8 T细胞可以通过未知的机制抑制vvg引发小鼠中th2介导的肺嗜酸性粒细胞增多。利用我们追踪RSV g特异性CD4 T细胞的能力，我们将确定记忆性CD8 T细胞抑制RSV g诱导的肺嗜酸性粒细胞病的机制。重要的是，最近的工作提供了证据，证明vvG和FI-RSV免疫可能通过独特的机制诱导RSV疫苗增强的疾病。因此，我们还将确定rsv特异性记忆CD8 T细胞是否可以预防FI-RSV疫苗增强的疾病。本提案的总体目标是确定RSV特异性记忆CD8 T细胞如何抑制CD4 T细胞介导的RSV疫苗增强疾病和免疫病理的机制。我们提出以下具体目的：1)确定记忆性CD8 T细胞如何抑制RSV特异性记忆性Th2细胞和RSV疫苗增强的肺嗜酸性粒细胞增多；2)确定记忆性CD8 T细胞是否可以预防FI-RSV疫苗增强的疾病和肺损伤。RSV疫苗增强疾病的潜在机制尚不清楚。本研究旨在确定rsv特异性记忆CD8 T细胞在与人类疾病直接相关的模型系统中降低CD4 T细胞介导的免疫病理严重程度的作用。

DESCRIPTION (provided by applicant): Respiratory syncytial virus (RSV) is the leading cause of viral lower respiratory tract infection in infants and young children. In addition, RSV causes serious disease in elderly and immune compromised individuals. Immunization against RSV is associated with enhanced disease and pulmonary eosinophilia following natural infection that is thought to be caused by an exuberant memory CD4 Th2 response. As a consequence, there is currently no approved RSV vaccine and detailed studies directed towards prevention of vaccine-associated disease are a necessary first step in the development of a safe and effective vaccine. The BALB/c mouse model of RSV infection faithfully mimics the human respiratory disease including the development of extensive lung inflammation and injury, pulmonary eosinophilia, and enhanced disease in mice previously immunized with either formalin inactivated (FI)-RSV or a recombinant vaccinia virus (vv) that expresses the attachment (G) glycoprotein. Memory CD4 T cells secreting Th2 cytokines are necessary for this response because their depletion eliminates eosinophilia. Recent studies have demonstrated that RSV- specific CD8 T cells can inhibit Th2-mediated pulmonary eosinophilia in vvG-primed mice by as yet unknown mechanisms. By taking advantage of our ability to track RSV G-specific CD4 T cells, we will determine the mechanism of memory CD8 T cell inhibition of RSV G-induced pulmonary eosinophilia. Importantly, recent work has provided evidence that vvG and FI-RSV immunization may induce RSV vaccine-enhanced disease via unique mechanisms. Therefore, we will also ascertain if RSV-specific memory CD8 T cells can prevent FI-RSV vaccine-enhanced disease. The overall goal of this proposal is to define the mechanism(s) of how RSV-specific memory CD8 T cells inhibit CD4 T cell-mediated RSV vaccine-enhanced disease and immunopathology. We propose the following Specific Aims: 1) To determine the how memory CD8 T cells inhibit RSV-specific memory Th2 cells and RSV vaccine-enhanced pulmonary eosinophilia and, 2) To determine if memory CD8 T cells can prevent FI-RSV vaccine-enhanced disease and pulmonary injury. The underlying mechanisms of RSV vaccine-enhanced disease remain unclear. The studies in this proposal are designed to determine the role of RSV-specific memory CD8 T cells in decreasing the severity of CD4 T cell-mediated immunopathology in a model system with direct relevance to human disease.