Immunopathology mediated by RSV-specific CD4 T cells

描述(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会导致老年人和免疫功能受损的人患上严重疾病。针对RSV的免疫与自然感染后的疾病加重和肺嗜酸性粒细胞增多有关，自然感染被认为是由旺盛的记忆力、CD4和Th2反应引起的。因此，目前还没有批准的RSV疫苗，针对疫苗相关疾病预防的详细研究是开发安全有效疫苗的必要的第一步。呼吸道合胞病毒感染的BALB/c小鼠模型忠实地模拟了人类呼吸道疾病的发展，包括广泛的肺部炎症和损伤，肺嗜酸性粒细胞增多，以及以前用福尔马林灭活(FI)-RSV或表达附着(G)糖蛋白的重组痘苗病毒(Vv)免疫的小鼠的增强性疾病。分泌Th2细胞因子的记忆CD4T细胞是这种反应所必需的，因为它们的耗尽消除了嗜酸性粒细胞增多。最近的研究表明，RSV特异性CD8T细胞可以抑制VVG诱导的小鼠Th2介导的肺嗜酸性粒细胞增多，其机制尚不清楚。利用我们追踪RSV G特异性CD4T细胞的能力，我们将确定记忆CD8T细胞抑制RSV G诱导的肺嗜酸性粒细胞增多症的机制。重要的是，最近的工作提供了证据，表明VVG和FI-RSV免疫可能通过独特的机制诱导RSV疫苗增强型疾病。因此，我们还将确定RSV特异性记忆CD8T细胞是否可以预防FI-RSV疫苗增强型疾病。这项建议的总体目标是确定RSV特异性记忆CD8T细胞如何抑制CD4T细胞介导的RSV疫苗增强型疾病和免疫病理学的机制(S)。我们提出了以下具体目标：1)确定记忆CD8 T细胞如何抑制RSV特异性记忆Th2细胞和RSV疫苗增强的肺嗜酸性粒细胞；2)确定记忆CD8 T细胞是否可以预防FI-RSV疫苗增强型疾病和肺损伤。RSV疫苗增强疾病的潜在机制尚不清楚。这项建议中的研究旨在确定RSV特异性记忆CD8T细胞在降低与人类疾病直接相关的模型系统中CD4T细胞介导的免疫病理学严重程度方面的作用。

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.