Presentation of Qa-1 restricted peptides during homeostasis and viral infection

Qa-1 限制性肽在稳态和病毒感染期间的呈现

基本信息

批准号：
10542654
负责人：
LAURENT COSCOY
金额：
$ 3.14万
依托单位：
UNIVERSITY OF CALIFORNIA BERKELEY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10542654
关键词：
Affinity Age Agonist Aminopeptidase Antigen Presentation Antigen Presentation Pathway Automobile Driving CD8-Positive T-Lymphocytes CD94 Antigen Cells Characteristics Cytomegalovirus Cytotoxic T-Lymphocytes Data Down-Regulation Family Generations Germ Lines Goals HIV vaccine Homeostasis Human Immune Immune Evasion In Vitro Infection KLRD1 gene Lead Ligands Light Macaca Mediating Modeling Mouse Strains Mus Natural Killer Cells Peptide Leader Sequences Peptide/MHC Complex Peptides Phenotype Play Positioning Attribute Principal Investigator Proteins Qa-1 Antigen Role SIV Vaccines Signal Transduction Splenocyte Stress Structure of thymic cortex Structure of thymic medulla T cell response T-Lymphocyte Techniques Testing Thymus Gland Tissues Transgenic Mice Tumor Immunity Up-Regulation Vaccine Design Vaccines Viral Virus Diseases Wild Type Mouse antigen processing base cell transformation cell type cooking cross reactivity immunoregulation in vivo insight interest member pathogen programs receptor response vector

项目摘要

Program Director/Principal Investigator (Robey, Ellen, A): Abstract: Mouse Qa-1 is a member of the conserved MHC-E family of non-classical MHC-1 molecules (MHC1b). In most cells, MHC-E presents peptides derived from the leader sequences of classical (MHC1a) molecules, and regulates the function of NK cells through the germ-line encoded receptor CD94/NKG2. MHC-E molecules can also present self and pathogen-derived peptides to CD8 T cells. The signals that lead to presentation of alternative peptides by MHC-E, and the functions of the responding CD8 T cells remain poorly understood. Recently, studies of a highly effective HIV vaccine based on a CMV vector revealed a prominent MHC-E restricted CD8 T cell response, raising new interest in understanding the presentation mechanisms and in vivo functions of MHC-E. Together with our collaborators, we have been investigating a Qa-1-restricted T cell response to cells lacking the ER aminopeptidase associated with antigen processing (ERAAP ko) (Nagarajan et al., 2012). The responding CD8 T cells recognize a 9-mer peptide derived from a self-protein (FL9 from FAM49) presented by Qa-1(b) (called QFL T cells). QFL T cells use an invariant TCR a, and have characteristics of both conventional and non-conventional CD8 T cells. Our preliminary data indicate that QFL T cells encounter high affinity Qa-1 restricted ligands at steady state and during viral infection. We propose to use a newly generated TCR transgenic mouse strain to probe the in vivo generation of Qa-1 restricted ligands for QFL T cells in both steady state and during viral infection. In Aim 1, we will identify the pMHC ligands involved in positive and agonist selection of QFL T cells, and will identify the thymic cell types that present the ligands. In Aim 2, we will identify the ligand(s) that drive the homeostatic expansion of QFL T cells, and will determine when, in what tissue, and by what cell type(s) they are presented. In Aim 3, we will determine the mechanisms that lead to priming of QFL T cells during MCMV infection, and will test whether QFL T cells induced during MCMV infection can kill infected cells and provide immune protection. Our results will shed new light on how MHC-E presentation regulates T cell responses, with important implications for vaccine design. OMB No. 0925-0001/0002 (Rev. 01/18 Approved Through 03/31/2020) Page Continuation Format Page

项目总监/首席研究员（Robey, Ellen, A）：抽象的：小鼠 Qa-1 是非经典 MHC-1 分子 (MHC1b) 保守 MHC-E 家族的成员。在大多数细胞，MHC-E 呈现源自经典 (MHC1a) 分子前导序列的肽，并且通过种系编码受体 CD94/NKG2 调节 NK 细胞的功能。 MHC-E分子可以还将自身肽和病原体衍生的肽呈递给 CD8 T 细胞。导致呈现的信号 MHC-E 替代肽，而响应 CD8 T 细胞的功能仍然知之甚少。最近，基于 CMV 载体的高效 HIV 疫苗的研究揭示了显着的 MHC-E 限制 CD8 T 细胞反应，引起人们对了解表达机制和体内的新兴趣 MHC-E 的功能。我们与我们的合作者一起研究了 Qa-1 限制性 T 细胞对细胞的反应缺乏与抗原加工相关的 ER 氨肽酶 (ERAAP ko) (Nagarajan et al., 2012)。这响应的 CD8 T 细胞识别源自自身蛋白（来自 FAM49 的 FL9）的 9 聚体肽， Qa-1(b)（称为 QFL T 细胞）。 QFL T 细胞使用不变的 TCR a，并具有两者的特征常规和非常规 CD8 T 细胞。我们的初步数据表明 QFL T 细胞遇到高在稳态和病毒感染期间，Qa-1 亲和力限制配体。我们建议使用新生成的 TCR 转基因小鼠品系可探测 QFL T 细胞 Qa-1 限制性配体的体内生成稳态和病毒感染期间。在目标 1 中，我们将鉴定参与阳性和阴性反应的 pMHC 配体。 QFL T 细胞的激动剂选择，并将鉴定呈递配体的胸腺细胞类型。在目标 2 中，我们将识别驱动 QFL T 细胞稳态扩增的配体，并确定何时、以什么方式组织，以及它们呈现的细胞类型。在目标 3 中，我们将确定导致的机制 MCMV 感染期间 QFL T 细胞的启动，并将测试 MCMV 期间是否诱导 QFL T 细胞感染可以杀死受感染的细胞并提供免疫保护。我们的结果将为 MHC-E 呈递如何调节 T 细胞反应提供新的线索，具有重要意义对疫苗设计的影响。 OMB 编号 0925-0001/0002（修订版 01/18 批准至 03/31/2020）页面延续格式页面