Modulation of CD8+ T Cell Responses by HLA-F

HLA-F 对 CD8 T 细胞反应的调节

• 批准号: 10366075
• 负责人: Jie Geng
• 金额: $ 23.4万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-09 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10366075
• 关键词: Address; Affinity; Alleles; Amino Acids; Antigen Presentation; Antigen Presentation Pathway; Antigens; Attention; Binding; Binding Sites; Blood group antigen f; CD8-Positive T-Lymphocytes; CD8B1 gene; CD94 Antigen; Cell surface; Cells; Complex; Development; Endoplasmic Reticulum; Ensure; Epitopes; Future; Genetic Polymorphism; Goals; HLA Antigens; HLA-A gene; HLA-B Antigens; Histocompatibility Antigens Class I; Human Herpesvirus 4; Immune; Immune response; Immunotherapy; Individual; Infection Control; Ligands; MHC Class I Genes; Molecular Chaperones; Molecular Conformation; Natural Killer Cells; Pathway interactions; Peptides; Population; Proteins; Provider; Specificity; T cell response; T-Cell Activation; T-Lymphocyte; Vaccine Design; Variant; Viral; Viral Cancer; Virus Diseases; antigen processing; antigen-specific T cells; antigenic peptide transporter; base; cancer immunotherapy; conformer; emerging pathogen; experience; fight against; invariant chain; neoplastic cell; pathogen; peripheral blood; recruit; trafficking; tumor; universal vaccine

CD8+ T cells are critical for clearance of viral-infected cells and tumor cells. They recognize antigens presented by human leukocyte antigen class I (HLA-I) molecules. HLA-F is a non-classical HLA-I molecule that has recently been drawing a lot of attention due to its potential significance in several viral infections and cancers. Although HLA-F was previously believed to be expressed only as open conformers (without peptide), recent studies showed that HLA-F can also be expressed as peptide-associated form. Due to its limited polymorphisms, HLA-F is an attractive target for viral infection control and cancer immunotherapy. However, it is still not clear whether and how HLA-F modulates the function of CD8+ T cells. In this proposal, we expect to address the function of HLA-F in CD8+ T cell responses with the following specific aims: Aim 1: Determine the HLA-F antigen presentation pathway. Both of the accumulation in the endoplasmic reticulum (ER) and the open conformation on the cell surface indicate peptide loading of HLA-F in the ER is inefficient. Our preliminary study suggests an unconventional antigen presentation pathway. We will determine where and how peptides are loaded to HLA-F, which will facilitate the future vaccine design. Aim 2: Determine the effect of HLA-F on CD8+ T cell activation. HLA-F specific CD8+ T cells will be isolated from peripheral blood of pathogen-experienced donors. The isolated CTLs will be used to investigate how HLA-F presents peptides to CTL. Since HLA-F is predominantly expressed as open conformers, we will also determine the effect of HLA-F open conformers on CD8+ T cell activation. Successful completion of this proposal will reveal the antigen presentation mechanisms of HLA-F and how HLA-F modulates CD8+ T cell responses, contributing to developing HLA-F based immunotherapies.

CD 8 + T细胞对于清除病毒感染的细胞和肿瘤细胞至关重要。它们识别抗原 人类白细胞抗原I类（HLA-I）分子。HLA-F是一种非经典的HLA-I分子， 最近由于其在几种病毒感染和癌症中的潜在意义而引起了很多关注。 虽然以前认为HLA-F仅表达为开放构象异构体（无肽），但最近发现， 研究表明，HLA-F也可以表达为肽相关形式。由于其有限 由于HLA-F基因多态性，HLA-F是病毒感染控制和癌症免疫治疗的有吸引力的靶标。但 目前尚不清楚HLA-F是否以及如何调节CD 8 + T细胞的功能。 在本提案中，我们期望通过以下方式来解决HLA-F在CD 8 + T细胞应答中的功能 具体目的：目的1：确定HLA-F抗原呈递途径。两种积累在 内质网（ER）和细胞表面上的开放构象表明HLA-F的肽负载， ER效率低下。我们的初步研究表明，一个非常规的抗原呈递途径。我们将 确定肽在哪里以及如何加载到HLA-F，这将有助于未来的疫苗设计。目标二： 确定HLA-F对CD 8 + T细胞活化的影响。HLA-F特异性CD 8 + T细胞将从以下分离： 有病原体经验的供体的外周血。分离的CTL将用于研究HLA-F 向CTL呈递肽。由于HLA-F主要表达为开放构象，我们还将 确定HLA-F开放构象异构体对CD 8 + T细胞活化的影响。 成功完成这一建议将揭示HLA-F的抗原提呈机制，以及如何 HLA-F调节CD 8 + T细胞应答，有助于开发基于HLA-F的免疫疗法。