Presentation of Listeria antigens to CD8+ T cells

将李斯特菌抗原呈递给 CD8 T 细胞

基本信息

批准号：
6628021
负责人：
John T Harty
金额：
$ 48.15万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-02-01 至 2006-01-31
项目状态：
已结题

项目摘要

DESCRIPTION (Verbatim from Applicant's Abstract): CD8+ T cells, which recognize pathogen derived peptides bound to MHC class I molecules, are important mediators of immunity to viral, protozoan and bacterial pathogens of humans. Infection of mice with Listeria monocytogenes (LM), a gram positive, enteric bacterial pathogen, provides an outstanding model to analyze the in vivo CD8+ T cell response to bacterial infection. Recently, we used recombinant Listeria (rLM), expressing a model antigen as a secreted or non-secreted molecule, to demonstrate that both secreted and non-secreted LM antigens primed CD8+ T cell responses under vaccine conditions but only the secreted antigen was a target for protective CD8+ T cells in previously immunized mice. We hypothesize that this dichotomy between CD8+ T cell priming and protective immunity, based on antigen location, results from previously unappreciated differences in the roles of endogenous and exogenous MHC class I antigen presentation pathways. These differences were only revealed by using precisely characterized rLM, expressing the same antigen in different bacterial locations, and the in vivo analysis of CD8+ T cell priming and protective immunity after LM infection. Thus, our goal is to use these rLM strains to increase our fundamental understanding of the in vivo role of endogenous and exogenous MHC class I presentation pathways in response to infection. We will use the rLM strains expressing defined CD8+ T cell epitopes in different bacterial locations to probe the function of endogenous and exogenous MHC class I antigen presentation pathways and address following Specific Aims: Specific Aim 1. Determine the relationship between in vivo epitope levels, CD8+ T cell priming and CD8+ T cell protective immunity against LM. Specific Aim 2. Identify the cell types that present the non-secreted antigens in vivo. Specific Aim 3. Determine the capacity of dendritic cells (DCs) to present secreted and non-secreted LM antigens to CD8+ T cells after infection or through cross-presentation. Specific Aim 4. Determine the requirement for CD4O and neutrophils for in vivo presentation of non-secreted bacterial antigens to CD8+ T cells. Results of these studies will provide important fundamental information regarding the in vivo roles of endogenous and exogenous MHC class I presentation pathways in CD8+ T cell responses to infection. Such basic information will impact evolving strategies for rational vaccine design, addressing the utility of the various antigen presentation pathways for vaccine delivery and for providing targets for protective immunity.

描述（逐字摘自申请人摘要）：CD8+ T 细胞，可识别与 MHC I 类分子结合的病原体衍生肽非常重要对人类病毒、原生动物和细菌病原体的免疫介质。小鼠感染单核细胞增生李斯特菌（LM），一种革兰氏阳性肠溶菌细菌病原体，提供了一个出色的模型来分析体内 CD8+ T 细胞对细菌感染的反应。最近，我们使用重组李斯特菌 (rLM)，将模型抗原表达为分泌或非分泌分子，以证明分泌型和非分泌型 LM 抗原都会引发 CD8+ T 细胞在疫苗条件下产生反应，但只有分泌的抗原是目标用于先前免疫小鼠的保护性 CD8+ T 细胞。我们假设 CD8+ T 细胞启动和保护性免疫之间的这种二分法基于抗原位置，是由于以前未意识到的差异造成的内源性和外源性 MHC I 类抗原呈递途径的作用。这些差异只能通过使用精确表征的 rLM 来揭示，在不同的细菌位置表达相同的抗原，并且在体内 LM 感染后 CD8+ T 细胞启动和保护性免疫分析。因此，我们的目标是利用这些 rLM 菌株来提高我们的基础了解内源性和外源性 MHC I 类的体内作用对感染的反应的表达途径。我们将使用 rLM 菌株在不同细菌位置表达确定的 CD8+ T 细胞表位探测内源性和外源性 MHC I 类抗原呈递的功能途径并解决以下具体目标：具体目标 1. 确定体内表位水平、CD8+ 之间的关系 T 细胞启动和 CD8+ T 细胞针对 LM 的保护性免疫。具体目标 2. 鉴定呈递非分泌抗原的细胞类型体内。具体目标 3. 确定树突状细胞 (DC) 的表达能力感染后针对 CD8+ T 细胞的分泌型和非分泌型 LM 抗原，或通过交叉演示。具体目标 4. 确定体内对 CD4O 和中性粒细胞的需求将非分泌性细菌抗原呈递给 CD8+ T 细胞。这些研究结果将提供重要的基本信息关于内源性和外源性 MHC I 类的体内作用 CD8+ T 细胞对感染反应的表达途径。这么基本的信息将影响合理疫苗设计的不断发展的策略，解决疫苗的各种抗原呈递途径的效用递送并提供保护性免疫的目标。