SCT PROBES FOR PATHOGEN IMMUNITY

用于病原体免疫的 SCT 探针

• 批准号: 8015194
• 负责人: TED Howard HANSEN
• 金额: $ 37.62万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-03-01 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8015194
• 关键词: Affinity; Antigen Presentation; Antigen-Presenting Cells; Antigens; Arthropods; Bacteria; Binding; CD81 gene; CD8B1 gene; Cell surface; Cells; Complex; Cross Presentation; DNA; DNA Vaccines; Disease; Disulfides; Engineering; Grant; Histocompatibility Antigens Class I; Immune system; Immunity; Infection; Membrane; Molecular; Mus; Pathway interactions; Peptides; Role; Secure; Skin; T cell response; T-Lymphocyte; Testing; Vaccination; Vaccines; Virus; base; beta-2 Microglobulin; design; efficacy testing; in vivo; lymph nodes; novel; novel strategies; pathogen; public health relevance; tumor; vaccine efficacy

DESCRIPTION (provided by applicant): Antigen presentation by MHC class I molecules to CD8 T cells is a major pathway by which the acquired immune system detects and eliminates virus infected cells. All nucleated cells express MHC class I molecules and are thus potentially capable of direct antigen presentation to CD8 T cells upon infection. However, several, but not all, recent studies suggest that predominantly DCs (or a specific subset of DCs) are uniquely required for in vivo priming of CD8 T cells to virus. Because pathogens may not directly infect these requisite DCs, cross presentation pathways have been proposed; in essence, the infected cell may not be the primary antigen presenting cell. Additionally, for many arthropod-transmitted viruses, virus-specific antigens may require transfer from migratory DCs in the skin to lymph node resident DCs to efficiently prime CD8 T cells. However, the mechanism by which pathogen-specific antigens are shuttled from the infected cells to DCs or between DC subsets is unknown. Not surprisingly, these same issues of direct presentation vs. cross-presentation also apply to CD8 T cell responses to tumors or following DNA vaccination. As a novel strategy to elicit pathogen immunity, we have engineered preprocessed and preloaded MHC class I molecules as single chains of peptide, beta-2 microglobulin and class I heavy chain. We have termed these complexes single chain trimers or SCTs. SCTs are very stably expressed at the cell surface and we and others have demonstrated that SCTs elicit a robust CD8 T cell response. In this grant we will test whether SCTs confer protective immunity against viruses and bacteria, and probe the cellular and molecular basis of vivo priming of CD8 T cells following SCT vaccination. Our hypothesis is that SCT vaccine efficacy results from crosspresentation by CD81 DCs using a novel mechanism involving intercellular membrane exchange. PUBLIC HEALTH RELEVANCE: Protective immunity to several pathogens requires that MHCI molecules bind antigenic peptides for presentation to CD8 T cells. However, to bind MHCI molecules, pathogen-derived peptides must compete with an extensive pool of endogenous peptides of the host. We have engineered MHCI molecules so that they can be pre-loaded with pathogen-derived peptides. In this grant, we will test the efficacy and mechanism of using these pre-loaded MHCI as vaccines.

描述(由申请人提供)：MHC-I类分子向CD8 T细胞递呈抗原是获得性免疫系统检测和清除病毒感染细胞的主要途径。所有有核细胞都表达MHC-I类分子，因此有可能在感染后直接向CD8T细胞递呈抗原。然而，最近的一些研究表明，主要是DC(或DC的一个特定子集)是体内CD8T细胞对病毒的启动所唯一需要的。因为病原体可能不会直接感染这些必需的DC，所以已经提出了交叉提呈途径；本质上，受感染的细胞可能不是主要的抗原提呈细胞。此外，对于许多节肢动物传播的病毒来说，病毒特异性抗原可能需要从皮肤中的迁移性DC转移到淋巴驻留的DC上，以有效地激活CD8T细胞。然而，病原体特异性抗原如何从受感染的细胞穿梭到DC或DC亚群之间的机制尚不清楚。毫不奇怪，这些直接呈现与交叉呈现的相同问题也适用于CD8T细胞对肿瘤或DNA疫苗接种后的反应。作为一种诱导病原体免疫的新策略，我们将MHC I类分子作为多肽、β-2微球蛋白和I类重链的单链进行了工程处理和预加载。我们称这些络合物为单链三聚体或SCTS。SCT在细胞表面非常稳定地表达，我们和其他人已经证明SCT能激发强大的CD8 T细胞反应。在这项资助中，我们将测试SCT是否具有对病毒和细菌的保护性免疫力，并探索SCT接种后CD8T细胞体内启动的细胞和分子基础。我们的假设是，SCT疫苗的效力是由CD81树突状细胞利用一种涉及细胞间膜交换的新机制进行交叉压力的结果。 公共卫生相关性：对几种病原体的保护性免疫需要MHCI分子结合抗原肽以呈递给CD8T细胞。然而，为了结合MHCI分子，病原体来源的多肽必须与宿主的大量内源性多肽竞争。我们已经对MHCI分子进行了改造，使其可以预先加载病原体衍生的多肽。在这笔赠款中，我们将测试使用这些预先加载的MHCI作为疫苗的效果和机制。