TLR Signaling in CD8 T Cell Response to Vaccinia Virus

CD8 T 细胞对痘苗病毒反应中的 TLR 信号转导

• 批准号: 7761753
• 负责人: Yiping Yang
• 金额: $ 19.31万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7761753
• 关键词: Affect; Antigen-Presenting Cells; Attenuated Vaccines; CD8B1 gene; Cell Maturation; Cells; Clonal Expansion; Communicable Diseases; Dendritic Cell Vaccine; Dendritic Cells; Development; Generations; HIV; Human; Immune; Immune system; Immunity; Immunodominant Epitopes; Immunology; In Vitro; Influenza; Lead; Life; Ligation; Light; Malaria; Malignant Neoplasms; Mediating; Memory; Natural Immunity; Outcome Study; Pathway interactions; Role; Safety; Shapes; Signal Transduction; Smallpox; Smallpox Vaccine; T cell response; T-Lymphocyte; Testing; Toll-Like Receptor 2; Vaccinated; Vaccines; Vaccinia virus; Virus Diseases; Work; adaptive immunity; base; cancer immunotherapy; combat; immunogenic; in vivo; neutralizing antibody; public health relevance; response; success

DESCRIPTION (provided by applicant): Vaccinia virus (VV) is the live vaccine responsible for successful eradication of smallpox worldwide. This success has led to development of recombinant VV as a vaccine vehicle for other infectious diseases and cancer. However, the development of VV vaccines for use in humans is limited by concerns about safety. Furthermore, the efficacy of VV vaccines has been limited by the pre-existing neutralizing antibodies in people who have been previously vaccinated against smallpox. Thus, there is a need to understand immunological mechanisms underlying the unique potency of VV vaccines, which in turn will help develop safer vaccines that are highly immunogenic but have minimal pathogenic potential. Recent advances in immunology have suggested a crucial role of the innate immune system in shaping adaptive immunity. We have shown that innate immune recognition of VV is mediated by Toll-like receptor 2 (TLR2) and dependent on MyD88 (a common adaptor for TLR signaling) and that the activation of TLR2-MyD88 pathway is critical for adaptive CD8 T cell immunity to VV in vivo. How activation of innate immunity promotes adaptive CD8 T cell responses to VV remains largely unknown. We have found in the preliminary studies that defective TLR signaling on APCs only moderately affected CD8 T cell priming, but not CD8 memory formation in response to VV infection in vivo and that direct TLR2 signaling on CD8 T cells enhanced their proliferation and survival in vitro. The objective of this application is to test the hypothesis that in addition to previously observed TLR-induced APC maturation, direct TLR2 signaling on CD8 T cells intrinsically is also critical for efficient CD8 T cell priming and formation of long- lived memory cells in vivo. Specifically, we will pursue the following two aims: 1) To test if direct TLR2-MyD88 signaling on CD8 T cells is required for their clonal expansion and effector differentiation following VV infection in vivo; 2) To define the role of intrinsic TLR2-MyD88 signaling in regulating the formation of long-lived memory CD8 T cells in response to VV infection in vivo. The outcome of these studies will not only shed light on how innate immunity modulates the formation of long-lived protective immunity, but more importantly, lead to the development of new generations of safer, effective vaccines to combat infectious diseases including smallpox, and cancer. PUBLIC HEALTH RELEVANCE: Vaccinia virus (VV) is the live smallpox vaccine responsible for successful eradication of smallpox worldwide. This success has led to development of recombinant VV as a vaccine vehicle for other infectious diseases and cancer. However, the development of VV vaccines for use in humans is limited by concerns about safety and reduced efficacy due to the pre-existing neutralizing antibodies in people who have been previously vaccinated against smallpox. Thus, there is a need to understand immunological mechanisms underlying the unique potency of VV vaccines, which in turn will help develop safer vaccines that are highly immunogenic but have minimal pathogenicpotential. The proposed work is to investigate immunological basis of live VV vaccines in the generation of effective and long-lasting CD8 T cell immunity, which in turn will lead to the development of new generations of safer vaccines to combat infectious diseases including smallpox, and cancer in humans.

描述（由申请人提供）：Vaccinia Virus（VV）是负责成功根除全球天花的实用疫苗。这种成功导致了重组VV作为其他传染病和癌症的疫苗的发展。但是，用于人类使用的VV疫苗的开发受到对安全的担忧的限制。此外，VV疫苗的功效受到了先前已接种过天花接种的人的中和抗体的限制。因此，有必要了解VV疫苗独特效力的背后的免疫机制，而VV疫苗的独特效力将有助于开发高度免疫原性但具有最小致病潜力的更安全的疫苗。免疫学的最新进展表明，先天免疫系统在塑造适应性免疫方面起着至关重要的作用。我们已经表明，VV的先天免疫识别是由Toll样受体2（TLR2）介导的，并依赖于MyD88（用于TLR信号的常见衔接子），并且TLR2-MYD88途径的激活对于适应性CD8 T细胞免疫至关重要。先天免疫的激活如何促进自适应CD8 T细胞对VV的反应仍然很大未知。我们在初步研究中发现，在APC上有缺陷的TLR信号仅适度影响CD8 T细胞启动，而不是在体内响应VV感染的CD8记忆形成，而CD8 T细胞上的TLR2信号直接增强了其在体内的增殖和生存。该应用的目的是检验以下假设：除了先前观察到的TLR诱导的APC成熟外，CD8 T细胞上的直接TLR2信号在本质上对有效的CD8 T细胞启动和体内长寿命记忆细胞的形成也至关重要。具体而言，我们将追求以下两个目的：1）测试CD8 T细胞上是否需要直接的TLR2-MYD88信号传导，以使其在Vivo中VV感染后其克隆膨胀和效应子分化； 2）定义固有的TLR2-MYD88信号传导在调节体内VV感染的长期记忆CD8 T细胞形成中的作用。这些研究的结果不仅会阐明先天免疫如何调节长寿保护性免疫的形成，而且更重要的是，导致新一代的更安全，有效的疫苗开发以对抗包括天花和癌症在内的感染性疾病。公共卫生相关性：Vaccinia病毒（VV）是负责成功消除全球天花的现场天花疫苗。这种成功导致了重组VV作为其他传染病和癌症的疫苗的发展。然而，由于先前已经接种过天花接种的人的中和抗体而导致的安全性中和抗体引起的安全性和疗效降低的关注，用于人类使用的VV疫苗的开发受到限制。因此，有必要理解VV疫苗独特效力的背后的免疫机制，而VV疫苗的独特效力将有助于开发高度免疫原性但具有最小病原体电位的更安全的疫苗。拟议的工作是在产生有效和持久的CD8 T细胞免疫力中研究活体VV疫苗的免疫学基础，这反过来又将导致新一代的更安全的疫苗来对抗包括天花和人类癌症在内的传染病。