Pathways of Antigen Presentation to CD8 T Cells In Vivo

体内抗原呈递至 CD8 T 细胞的途径

• 批准号: 7163505
• 负责人: Christopher C Norbury
• 金额: $ 30.27万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-15 至 2008-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7163505
• 关键词: Adenovirus Vector; Adenoviruses; Affect; Antigen Presentation; Antigen Presentation Pathway; Antigen Targeting; Antigen-Presenting Cells; Antigens; Authorization documentation; Bacterial Infections; CD4 Positive T Lymphocytes; CD8B1 gene; Cells; Characteristics; Cities; Complex; Cross Presentation; Cross-Priming; Dendritic Cells; Disclosure; Effector Cell; Epithelium; Epitopes; Face; Generations; Genes; Goals; Histocompatibility Antigens Class I; Human Resources; Immune response; Immunotherapeutic agent; In Vitro; Infection; Instruction; Last Name; Late Promoters; Life; Life Cycle Stages; Lung; Lymphoid; MHC Class I Genes; Mediating; Medical center; Medicine; Modeling; Molecular; Names; Numbers; Organ; Pathway interactions; Pennsylvania; Peptide/MHC Complex; Peptides; Phenotype; Principal Investigator; Printing; Process; Property; Protein C; Proteins; Regulation; Research; Research Project Grants; Role; Route; Site; Skin; Surface Antigens; T-Lymphocyte; Thinking; Thymus Gland; Time; Tissues; Universities; Vaccine Design; Vaccinia; Vaccinia virus; Viral; Viral Antigens; Virus; antigen processing; base; college; immunogenicity; in vivo; macrophage; multicatalytic endopeptidase complex; promoter; protein expression; recombinant virus; response; surfactant; tumor; tumorigenic; uptake

CD8+ T cells are critical components of the anti-viral immune response to some viruses. Naive CD8+ T cells differentiate into effector cells only after recognition of peptide-MHC Class I complexes on the surface of antigen presenting cells (APC). The peptides presented can be generated from protein antigens via a number of pathways in vivo. Peptides can be produced from antigens expressed within a virus-infected APC, when presentation is termed direct-priming. Alternatively, peptides can be produced from proteins that are transferred from other cells to APC prior to presentation, a process known as cross-priming. The extent to which direct-priming or cross-priming contribute to activation of naive CD8+ T cells in vivo is not known. The overall objective of this project is to delineate the mechanisms used to generate MHC Class I-peptide complexes during priming of naive CD8+ T cells in vivo. Our underlying hypothesis is that alteration in protein expression can, and does, direct in vivo antigen presentation into direct or cross-priming pathways. To examine this issue we will use recombinant viruses to express multiple protein antigens and will analyze antigen presentation to naive and effector CD8+ T cells both in vitro and in vivo.ln Aim 1 we will determine the effects of targeting viral antigen for expression in specific tissues on the pathways of antigen presentation used in vivo. We will examine the timing and efficiency of CD8+ T cell priming to ubiquitously expressed or tissue-targeted antigen. We will also identify the APC responsible for priming via each route, and examine the properties of this APC that are necessary for effective priming. In Aim 2 we will examine differential antigen presentation as a mechanism for the reduced immunogenicity of virus genes expressed late in the virus life cycle. In addition, by using a natural example of antigen shuttled into different antigen presentation ;)athways in vivo we will compare the efficiency of CD8+ T cell priming via direct or cross-priming to the mount of antigen made in vivo. In Aim 3 we will determine, in vitro and in vivo, the characteristics of proteins that are preferentially transferred from virus-infected cells to APC during cross-priming. Delineation of the mechanisms governing the use of different antigen presentation pathways in vivo will provide a basis for the rational design of vaccines and immunotherapeutic strategies aimed at induction of protective CD8+ T cells. _ERFORMANCE SITE(S) (organization, city, state) The Milton S. Hershey Medical Center The Pennsylvania State University Hershey, PA KEY PERSONNEL. See instructions. Use continuation pages as needed to provide the required information Start with Principal Investigator. List all other key personnel in alphabetical order, last name firsL Name Organization Christopher C. Norbury Penn State College of Medicine Hershey, PA Disclosure Permission StatemenL Applicable to SBIR/STTR Only. See instructions. [] Yes [] PHS 398 (Rav. 05/01) Page _2_ in the format shown below. Role on Project Principal Investigator No Form Page 2 Principal InvestigatodProgram Director(Last, first, middle): Norbury, Christopher C. The name of the pdncipal investigatodprogram director must be provided at the top of each printed page and each continuation page. RESEARCH GRANT TABLE OF CONTENTS Page Numbers Face Page .................................................................................................................................................. 1 Description,

CD8+T细胞是某些病毒的抗病毒免疫反应的重要组成部分。原始CD8+T细胞 只有在识别细胞表面的多肽-MHC-I类复合体后才能分化为效应细胞 抗原提呈细胞(APC)。所呈现的多肽可以由蛋白质抗原通过 体内途径的数量。多肽可以由病毒感染的APC内表达的抗原产生， 当呈现被称为直接启动时。或者，可以从以下蛋白质中产生多肽 在提呈前从其他细胞转移到APC，这一过程被称为交叉启动。达到的程度 目前尚不清楚体内初始CD8+T细胞激活的机制是直接启动还是交叉启动。这个 该项目的总体目标是描述用于产生MHC I类多肽的机制 体内初始CD8+T细胞活化过程中的复合体。我们的基本假设是蛋白质的变化 表达可以并且确实将体内的抗原递送导向直接或交叉启动的途径。至 研究这一问题我们将使用重组病毒表达多种蛋白质抗原，并将分析 在体外和体内，抗原递呈给幼稚的和效应的CD8+T细胞。 靶向病毒抗原在特定组织中表达对抗原提呈途径的影响 在体内使用。我们将研究CD8+T细胞对无处不在表达或 组织靶向抗原。我们还将确定负责通过每条路线进行引爆的APC，并检查 有效引爆所必需的这种APC的特性。在目标2中，我们将研究差异 抗原提呈是晚期表达的病毒基因免疫原性降低的机制 病毒生命周期。此外，通过使用一个自然的抗原穿梭到不同的抗原呈现方式的例子 在体内，我们将比较CD8+T细胞通过直接或交叉激发与 体内制造的抗原的载体。在目标3中，我们将在体外和体内确定蛋白质的特性 在交叉启动过程中优先从感染病毒的细胞转移到APC。国家地理信息系统 体内不同抗原提呈途径的使用机制将为 合理设计疫苗和免疫治疗策略，以诱导保护性CD8+T细胞。 _ERFORMANCE SITE(S)(组织、市、州) 米尔顿·S·好时医疗中心 宾夕法尼亚州立大学 宾夕法尼亚州好时 关键人员。请参阅说明。根据需要使用续页提供所需信息 从首席调查员开始。按字母顺序列出所有其他关键人员，姓前 名称：组织 克里斯托弗·C·诺伯里宾夕法尼亚州立医学院 宾夕法尼亚州好时 披露许可状态仅适用于SBIR/STTR。请参阅说明。[]是[] PHS 398(Rav.05/01)第_2页_ 格式如下所示。 在项目中的角色 首席调查员 不是 表单第2页 首席调查项目主任(最后、第一、中间)：诺伯里，克里斯托弗·C 必须在每张打印页和每张续页的顶部提供pdncipal调查项目主管的姓名。 研究补助金 目录 页码 主页........................................................................................................................1 描述，