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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：
10591419
负责人：
LAURENT COSCOY
金额：
$ 57.48万
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/10591419
关键词：
Affinity Age Agonist Aminopeptidase Antigen Presentation Antigen Presentation Pathway Automobile Driving Binding CD8-Positive T-Lymphocytes CD94 Antigen Cells Characteristics Cytomegalovirus Cytotoxic T-Lymphocytes Data Down-Regulation Family Generations Goals HIV vaccine Homeostasis Homologous Gene Human Immune Immune Evasion In Vitro Infection KLRD1 gene Ligands 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 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）：