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

• 批准号: 10379603
• 负责人: LAURENT COSCOY
• 金额: $ 4.97万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10379603
• 关键词: Affinity; Agonist; Aminopeptidase; CD8-Positive T-Lymphocytes; Cells; Characteristics; Cytomegalovirus; Data; Family; Generations; HIV vaccine; Homeostasis; Immune; Infection; Lead; Ligands; Light; Mouse Strains; Mus; Natural Killer Cells; Peptide/MHC Complex; Peptides; Play; Principal Investigator; Proteins; Qa-1 Antigen; Signal Transduction; T cell response; T-Lymphocyte; Testing; Thymus Gland; Tissues; Transgenic Mice; Vaccine Design; Virus Diseases; antigen processing; base; cell type; immunoregulation; in vivo; interest; member; pathogen; programs; receptor; vector

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 receptors NKG2A and NKG2C. 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:2012cn}. The responding CD8 T cells recognize a 9-mer peptide derived from a self-protein (FL9 from FAM49B) presented by Qa-1(b) (called QFL T cells). QFL T cells use a semi-invariant TCR alpha chain, 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

项目主任/首席调查员(罗比，艾伦，A)： 摘要： 小鼠Qa-1是非经典MHC-1分子(MHC1b)中保守的MHC-E家族成员。在……里面 大多数细胞，MHC-E提供源自经典(MHC1a)分子的前导序列的肽，以及 通过受体NKG2A和NKG2C调节NK细胞的功能。MHC-E分子也可以 将自身和病原体来源的多肽呈递给CD8T细胞。导致提出替代方案的信号 MHC-E的多肽以及应答的CD8T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MHC-E限制的CD8 T细胞反应，引起了人们对理解T细胞递呈机制和体内功能的新兴趣 MHC-E 与我们的合作者一起，我们一直在研究Qa-1限制的T细胞对细胞的反应 缺乏与抗原处理相关的ER氨基肽酶(ERAAP Ko)[Nagarajan：2012cn}。这个 反应性CD8 T细胞识别来自自身蛋白(FAM49B的Fl9)的9肽 Qa-1(B)(称为QFL T细胞)。QFL T细胞使用半不变的TCRα链，并具有以下特征 包括常规和非常规CD8T细胞。我们的初步数据表明QFL T细胞遇到 稳定状态和病毒感染期间的高亲和力Qa-1限制性配体。我们建议使用一种新的 构建TCR转基因小鼠品系探索Qa-1限制性QFL T配体的体内生成 处于稳定状态和病毒感染期间的细胞。在目标1中，我们将确定参与的pMHC配体 QFL T细胞的阳性和激动剂选择，并将识别呈现配体的胸腺细胞类型。在……里面 目的2，我们将确定驱动QFL T细胞动态平衡扩张的配体(S)，并将确定 它们何时、在什么组织中、由什么细胞类型(S)呈现。在目标3中，我们将确定机制 这将导致MCMV感染期间QFL T细胞的启动，并将测试QFL T细胞在感染MCMV期间是否诱导 MCMV感染可以杀死被感染的细胞，并提供免疫保护。 我们的结果将为MHC-E如何调节T细胞反应提供新的线索，具有重要的意义 对疫苗设计的影响。 OMB编号0925-0001/0002(01/18修订版批准至2020年3月31日)页面续格式页面